Pyrazolo piperidine derivatives as NADPH oxidase inhibitors

ABSTRACT

The present invention is related to pyrazolo piperidine derivatives of Formula (I), pharmaceutical composition thereof and to their use for the treatment and/or prophylaxis of disorders or conditions related to Nicotinamide adenine dinucleotide phosphate oxidase (NADPH Oxidase).

CROSS-REFERENCE TO RELATED APPLICATION

This application is the U.S. national stage application of InternationalPatent Application No. PCT/IB2011/050668, filed Feb. 17, 2011.

FIELD OF THE INVENTION

The present invention relates to pyrazolo piperidine derivatives ofFormula (I), pharmaceutical composition thereof and to their use for thepreparation of a medicament for the treatment and/or prophylaxis ofcardiovascular diseases, respiratory disorders, disorders affecting themetabolism, skin and/or bone diseases, neurodegenerative diseases,kidney diseases, reproduction disorders, inflammatory disorders andcancers. Specifically, the present invention is related to pyrazolopiperidine derivatives useful for the preparation of a pharmaceuticalformulation for the modulation, notably the inhibition of the activityor function of the Nicotinamide adenine dinucleotide phosphate oxidase(NADPH Oxidase).

BACKGROUND OF THE INVENTION

NADPH oxidases (NOX) are proteins that transfer electrons acrossbiological membranes. In general, the electron acceptor is oxygen andthe product of the electron transfer reaction is superoxide. Thebiological function of NOX enzymes is therefore the generation ofreactive oxygen species (ROS) from oxygen. Reactive oxygen species (ROS)are oxygen-derived small molecules, including oxygen radicals(super-oxide anion [^(•)O₂ ⁻], hydroxyl [HO^(•)], peroxyl [ROO^(•)],alkoxyl [RO^(•)] and hydroperoxyl [HOO^(•)]) and certain non-radicalsthat are either oxidizing agents and/or are easily converted intoradicals. Nitrogen-containing oxidizing agents, such as nitric oxide arealso called reactive nitrogen species (RNS). ROS generation is generallya cascade of reactions that starts with the production of superoxide.Superoxide rapidly dismutates to hydrogen peroxide either spontaneously,particularly at low pH or catalyzed by superoxide dismutase. Otherelements in the cascade of ROS generation include the reaction ofsuperoxide with nitric oxide to form peroxynitrite, theperoxidase-catalyzed formation of hypochlorous acid from hydrogenperoxide, and the iron-catalyzed Fenton reaction leading to thegeneration of hydroxyl radical.

ROS avidly interact with a large number of molecules including othersmall inorganic molecules as well as DNA, proteins, lipids,carbohydrates and nucleic acids. This initial reaction may generate asecond radical, thus multiplying the potential damage. ROS are involvednot only in cellular damage and killing of pathogens, but also in alarge number of reversible regulatory processes in virtually all cellsand tissues. However, despite the importance of ROS in the regulation offundamental physiological processes, ROS production can alsoirreversibly destroy or alter the function of the target molecule.Consequently, ROS have been increasingly identified as majorcontributors to damage in biological organisms, so-called “oxidativestress”.

During inflammation, NADPH oxidase is one of the most important sourcesof ROS production in vascular cells under inflammatory conditions(Thabut et al., 2002, J. Biol. Chem., 277:22814-22821).

In the lung, tissues are constantly exposed to oxidants that aregenerated either endogenously by metabolic reactions (e.g. bymitochondrial respiration or activation of recruited inflammatory cells)or exogenously in the air (e.g. cigarette smoke or air pollutants).Further, the lungs, constantly exposed to high oxygen tensions ascompared to other tissues, have a considerable surface area and bloodsupply and are particularly susceptible to injury mediated by ROS(Brigham, 1986, Chest, 89(6): 859-863). NADPH oxidase-dependent ROSgeneration has been described in pulmonary endothelial cells and smoothmuscle cells. NADPH oxidase activation in response to stimuli has beenthought to be involved in the development of respiratory disorders suchas pulmonary hypertension and enhancement of pulmonary vasoconstriction(Djordjevic et al., 2005, Arterioscler. Thromb. Vasc. Biol., 25,519-525; Liva et al., 2004, Am. J. Physiol. Lung, Cell. Mol. Physiol.,287: L111-118). Further, pulmonary fibrosis has been characterized bylung inflammation and excessive generation of ROS.

Osteoclasts, which are macrophage-like cells that play a crucial role inbone turn-over (e.g. bone resorption), generate ROS through NADPHoxidase-dependent mechanisms (Yang et al., 2002, J. Cell. Chem. 84,645-654).

Diabetes is known to increase oxidative stress (e.g. increasedgeneration of ROS by auto-oxidation of glucose) both in humans andanimals and increased oxidative stress has been said to play animportant role in the development of diabetic complications. It has beenshown that increased peroxide localization and endothelial celldysfunction in the central retina of diabetic rats coincides with theareas of NADPH oxidase activity in the retinal endothelial cells (Elliset al., 2000, Free Rad. Biol. Med., 28:91-101). Further, it has beensuggested that controlling oxidative stress (ROS) in mitochondria and/orinflammation may be a beneficial approach for the treatment of diabetes(Pillarisetti et al., 2004, Expert Opin. Ther. Targets, 8(5):401-408).

ROS are also strongly implicated in the pathogenesis of atherosclerosis,cell proliferation, hypertension and reperfusion injury cardiovasculardiseases in general (Cai et al., 2003, Trends Pharmacol. Sci.,24:471-478). Not only is superoxide production, for example in thearterial wall, increased by all risk factors for atherosclerosis, butROS also induce many “proatherogenic” in vitro cellular responses. Animportant consequence of the formation of ROS in vascular cells is theconsumption of nitric oxide (NO). NO inhibits the development ofvascular diseases, and loss of NO is important in the pathogenesis ofcardiovascular diseases. The increase in NADPH oxidase activity invascular wall after balloon injury has been reported (Shi et al., 2001,Throm. Vasc. Biol., 2001, 21, 739-745)

It is believed that oxidative stress or free radical damage is also amajor causative factor in neurodegenerative diseases. Such damages mayinclude mitochondrial abnormalities, neuronal demyelination, apoptosis,neuronal death and reduced cognitive performance, potentially leading tothe development of progressive neurodegenerative disorders (Nunomura etal., 2001, J. Neuropathol. Exp. Neurol., 60:759-767; Girouard, 2006, J.Appl. Physiol. 100:328-335).

Further, the generation of ROS by sperm has been demonstrated in a largenumber of species and has been suggested to be attributed to an NADPHoxidase within spermatozoa (Vernet et al., Biol. Reprod., 2001,65:1102-1113). Excessive ROS generation has been suggested to beimplicated in sperm pathology, including male infertility and also insome penile disorders and prostate cancer.

NADPH oxidases are multi-subunit enzymes made up of a membrane-boundcytochrome b558 domain and three cytosolic protein subunits, p47phox,p67phox and a small GTPase, Rac. Seven isoforms of NOX enzymes have beenidentified including NOX1, NOX2, NOX3, NOX4, NOX5, DUOX1 and DUOX2 (Letoet al., 2006, Antioxid. Redox Signal, 8(9-10):1549-61; Cheng et al.,2001, Gene, 16; 269(1-2):131-40).

Thus, ROS derived from NADPH contribute to the pathogenesis of numerousdiseases, especially cardiovascular diseases or disorders, respiratorydisorder or disease, disease or disorder affecting the metabolism, bonedisorders, neurodegenerative diseases, inflammatory diseases,reproduction disorder or disease, pain, cancer and disease or disordersof the gastrointestinal system. Therefore, it would be highly desirableto develop new active agents focusing on the ROS signalling cascade,especially on NADPH oxidases (NOX).

SUMMARY OF THE INVENTION

The present invention is directed towards new molecules useful in thetreatment and/or prophylaxis of Nicotinamide adenine dinucleotidephosphate oxidase (NADPH Oxidase) related disorders such ascardiovascular diseases, respiratory disorders, disorders affecting themetabolism, skin and/or bone diseases, neurodegenerative diseases,kidney diseases, reproduction disorders, inflammatory disorders,cancers, allergic disorders, traumatisms, septic, hemorrhagic andanaphylactic shock, diseases or disorders of the gastrointestinalsystem, angiogenesis and angiogenesis-dependent conditions. Notably, theinvention is related to new molecules useful in the inhibition orreduction of ROS production in cells.

A first aspect of the invention provides a pyrazolo piperidinederivative according to Formula (I), wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷,R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are as defined below,as well as tautomers, geometrical isomers, optically active forms,pharmaceutically acceptable salts and pharmaceutically active derivativethereof with the proviso that the compound is not selected from thegroup consisting of:

-   6-methyl-2-phenyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   6-benzyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one    (RN=909187-64-0); and-   6-benzyl-2,3a,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one    (RN=62458-89-3).

A second aspect of the invention relates to a pyrazolo piperidinederivative according to Formula (I), wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷,R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are as defined below,as well as tautomers, geometrical isomers, optically active forms,pharmaceutically acceptable salts and pharmaceutically active derivativethereof for use as a medicament.

A third aspect of the invention relates to a pharmaceutical compositioncontaining at least one a pyrazolo piperidine derivative according tothe invention, as well as tautomers, geometrical isomers, opticallyactive forms, pharmaceutically acceptable salts and pharmaceuticallyactive derivative thereof.

A fourth aspect of the invention resides in a use of a pyrazolopiperidine derivative according to the invention as tautomers,geometrical isomers, optically active forms, pharmaceutically acceptablesalts and pharmaceutically active derivative thereof for the preparationof a pharmaceutical composition for the treatment or prophylaxis of adisease or condition selected from cardiovascular disorders, respiratorydisorders, metabolism disorders, skin disorders, bone disorders,neuroinflammatory and/or neurodegenerative disorders, kidney diseases,reproduction disorders, diseases affecting the eye and/or the lensand/or conditions affecting the inner ear, inflammatory disorders, liverdiseases, pain, cancers, allergic disorders, traumatisms, septic,hemorrhagic and anaphylactic shock, diseases or disorders of thegastrointestinal system, angiogenesis and angiogenesis-dependent and/orother diseases and disorders associated with Nicotinamide adeninedinucleotide phosphate oxidase (NADPH Oxidase).

A fifth aspect of the invention relates to a method for treating apatient suffering from a disease or condition selected fromcardiovascular disorders, respiratory disorders, metabolism disorders,skin disorders, bone disorders, neuroinflammatory and/orneurodegenerative disorders, kidney diseases, reproduction disorders,diseases affecting the eye and/or the lens and/or conditions affectingthe inner ear, inflammatory disorders, liver diseases, pain, cancers,allergic disorders, traumatisms, septic, hemorrhagic and anaphylacticshock, diseases or disorders of the gastrointestinal system,angiogenesis and angiogenesis-dependent and other diseases and/ordisorders associated with Nicotinamide adenine dinucleotide phosphateoxidase (NADPH Oxidase). The method comprises administering a pyrazolopiperidine derivative according to Formula (I), wherein R¹, R², R³, R⁴,R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are asdefined below as well as tautomers, geometrical isomers, opticallyactive forms, pharmaceutically acceptable salts and pharmaceuticallyactive derivative thereof in a patient in need thereof.

A sixth aspect of the invention relates to a pyrazolo piperidinederivative according to Formula (I), wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷,R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are as defined below,as well as tautomers, geometrical isomers, optically active forms,pharmaceutically acceptable salts and pharmaceutically active derivativethereof for the treatment of a disease or condition selected fromcardiovascular disorders, respiratory disorders, metabolism disorders,skin disorders, bone disorders, neuroinflammatory and/orneurodegenerative disorders, kidney diseases, reproduction disorders,diseases affecting the eye and/or the lens and/or conditions affectingthe inner ear, inflammatory disorders, liver diseases, pain, cancers,allergic disorders, traumatisms, septic, hemorrhagic and anaphylacticshock, diseases or disorders of the gastrointestinal system,angiogenesis and angiogenesis-dependent and other diseases and/ordisorders associated with Nicotinamide adenine dinucleotide phosphateoxidase (NADPH Oxidase).

Other features and advantages of the invention will be apparent from thefollowing detailed description.

DETAILED DESCRIPTION OF THE INVENTION

The following paragraphs provide definitions of the various chemicalmoieties that make up the compounds according to the invention and areintended to apply uniformly through-out the specification and claims,unless an otherwise expressly set out definition provides a broaderdefinition.

The term “alkyl” when used alone or in combination with other terms,comprises a straight chain or branched C₁-C₂₀ alkyl which refers tomonovalent alkyl groups having 1 to 20 carbon atoms. This term isexemplified by groups such as methyl, ethyl, n-propyl, i-propyl,n-butyl, s-butyl, i-butyl, t-butyl, n-pentyl, 1-ethylpropyl,2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, n-hexyl,2-methylpentyl, 3-methylpentyl, 4-methylpentyl, n-heptyl, 2-methylhexyl,3-methylhexyl, 4-methylhexyl, 5-methylhexyl, n-heptyl, n-octyl, n-nonyl,n-decyl, tetrahydrogeranyl, n-dodecyl, n-tridecyl, n-tetradecyl,n-pentadecyl, n-hexadecyl, n-octadecyl, n-nonadecyl, and n-eicosanyl andthe like. Preferably, these include C₁-C₉ alkyl, more preferably C₁-C₆alkyl, especially preferably C₁-C₄ alkyl, which, by analogy, referrespectively to monovalent alkyl groups having 1 to 9 carbon atoms,monovalent alkyl groups having 1 to 6 carbon atoms and monovalent alkylgroups having 1 to 4 carbon atoms. Particularly, those include C₁-C₆alkyl.

The term “alkenyl” when used alone or in combination with other terms,comprises a straight chain or branched C₂-C₂₀ alkenyl. It may have anyavailable number of double bonds in any available positions, and theconfiguration of the double bond may be the (E) or (Z) configuration.This term is exemplified by groups such as vinyl, allyl, isopropenyl,1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl,2-ethyl-1-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl,3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 1-octenyl, geranyl,1-decenyl, 1-tetradecenyl, 1-octadecenyl, 9-octadecenyl, 1-eicosenyl,and 3,7,11,15-tetramethyl-1-hexadecenyl, and the like. Preferably, theseinclude C₂-C₈ alkenyl, more preferably C₂-C₆ alkenyl. Among others,especially preferred are vinyl or ethenyl (—CH═CH₂), n-2-propenyl(allyl, —CH₂CH═CH₂), isopropenyl, 1-propenyl, 2-methyl-1-propenyl,1-butenyl, 2-butenyl, and 3-methyl-2-butenyl and the like. The term“alkynyl” when used alone or in combination with other terms, comprisesa straight chain or branched C₂-C₂₀ alkynyl. It may have any availablenumber of triple bonds in any available positions. This term isexemplified by groups such as alkynyl groups that may have a carbonnumber of 2-20, and optionally a double bond, such as ethynyl (—C≡CH),1-propynyl, 2-propynyl (propargyl: —CH₂C≡CH), 2-butynyl,2-pentene-4-ynyl, and the like. Particularly, these include C₂-C₈alkynyl, more preferably C₂-C₆ alkynyl and the like. Preferably thoseinclude C₂-C₆ alkynyl which refers to groups having 2 to 6 carbon atomsand having at least 1 or 2 sites of alkynyl unsaturation.

The term “heteroalkyl” refers to C₁-C₁₂-alkyl, preferably C₁-C₆-alkyl,wherein at least one carbon has been replaced by a heteroatom selectedfrom O, N or S, including 2-methoxy ethyl and the like.

The term “aryl” refers to an unsaturated aromatic carbocyclic group offrom 6 to 14 carbon atoms having a single ring (e.g., phenyl) ormultiple condensed rings (e.g., indenyl, naphthyl). Aryl include phenyl,naphthyl, anthryl, phenanthrenyl and the like.

The term “C₁-C₆ alkyl aryl” refers to aryl groups having a C₁-C₆ alkylsubstituent, including methyl phenyl, ethyl phenyl and the like.

The term “aryl C₁-C₆ alkyl” refers to C₁-C₆ alkyl groups having an arylsubstituent, including 3-phenylpropanyl, benzyl and the like.

The term “heteroaryl” refers to a monocyclic heteroaromatic, or abicyclic or a tricyclic fused-ring heteroaromatic group. Particularexamples of heteroaromatic groups include optionally substitutedpyridyl, pyrrolyl, pyrimidinyl, furyl, thienyl, imidazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadia-zolyl,1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-triazinyl, 1,2,3-triazinyl,benzofuryl, [2,3-dihydro]benzofuryl, isobenzofuryl, benzothienyl,benzotriazolyl, isobenzothienyl, indolyl, isoindolyl, 3H-indolyl,benzimidazolyl, imidazo[1,2-a]pyridyl, benzothiazolyl, benzoxa-zolyl,quinolizinyl, quinazolinyl, pthalazinyl, quinoxalinyl, cinnolinyl,napthyridinyl, pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl,pyrido[4,3-b]pyridyl, quinolyl, isoquinolyl, tetrazolyl,5,6,7,8-tetrahydroquinolyl, 5,6,7,8-tetrahydroisoquinolyl, purinyl,pteridinyl, carbazolyl, xanthenyl or benzoquinolyl.

The term “C₁-C₆ alkyl heteroaryl” refers to heteroaryl groups having aC₁-C₆ alkyl substituent, including methyl furyl and the like.

The term “heteroaryl C₁-C₆ alkyl” refers to C₁-C₆ alkyl groups having aheteroaryl substituent, including furyl methyl and the like.

The term “C₂-C₆ alkenyl aryl” refers to an aryl groups having a C₂-C₆alkenyl substituent, including vinyl phenyl and the like.

The term “aryl C₂-C₆ alkenyl” refers to a C₂-C₆ alkenyl groups having anaryl substituent, including phenyl vinyl and the like.

The term “C₂-C₆ alkenyl heteroaryl” refers to heteroaryl groups having aC₂-C₆ alkenyl substituent, including vinyl pyridinyl and the like.

The term “heteroaryl C₂-C₆ alkenyl” refers to C₁-C₆ alkenyl groupshaving a heteroaryl substituent, including pyridinyl vinyl and the like.

The term “C₃-C₈-cycloalkyl” refers to a saturated carbocyclic group offrom 3 to 8 carbon atoms having a single ring (e.g., cyclohexyl) ormultiple condensed rings (e.g., norbornyl). C₃-C₈-cycloalkyl includescyclopentyl, cyclohexyl, norbornyl and the like.

The term “heterocycloalkyl” refers to a C₃-C₈-cycloalkyl group accordingto the definition above, in which up to 3 carbon atoms are replaced byheteroatoms chosen from the group consisting of O, S, NR, R beingdefined as hydrogen or methyl. Heterocycloalkyl include pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl and the like.

The term “C₁-C₆ alkyl C₃-C₈-cycloalkyl” refers to C₃-C₈-cycloalkylgroups having a C₁-C₆ alkyl substituent, including methyl cyclopentyland the like.

The term “C₃-C₈-cycloalkyl C₁-C₆ alkyl” refers to C₁-C₆ alkyl groupshaving a C₃-C₈-cycloalkyl substituent, including 3-cyclopentyl propyland the like.

The term “C₁-C₆ alkyl heterocycloalkyl” refers to heterocycloalkylgroups having a C₁-C₆ alkyl substituent, including 4-methylpiperidinyland the like.

The term “heterocycloalkyl C₁-C₆ alkyl” refers to C₁-C₆ alkyl groupshaving a heterocycloalkyl substituent, including(1-methylpiperidin-4-yl)methyl and the like.

The term “carboxy” refers to the group —C(O)OH.

The term “carboxy C₁-C₆ alkyl” refers to C₁-C₆ alkyl groups having acarboxy substituent, including 2-carboxyethyl and the like.

The term “acyl” refers to the group —C(O)R where R includes H, “C₁-C₆alkyl,” preferably “C₁-C₆ alkyl,” “aryl,” “heteroaryl,”“C₃-C₈-cycloalkyl,” “heterocycloalkyl,” “aryl C₁-C₆ alkyl,” “heteroarylC₁-C₆ alkyl,” “C₃-C₈-cycloalkyl C₁-C₆ alkyl” or “heterocycloalkyl C₁-C₆alkyl”, including acetyl and the like.

The term “acyl C₁-C₆ alkyl” to C₁-C₆ alkyl groups having an acylsubstituent, including 2-acetylethyl and the like.

The term “acyl aryl” refers to aryl groups having an acyl substituent,including 2-acetylphenyl and the like.

The term “acyloxy” refers to the group —OC(O)R where R includes H,“C₁-C₆ alkyl”, “C₂-C₆ alkenyl,” “C₂-C₆ alkynyl,” “C₃-C₈-cycloalkyl,”“heterocycloalkyl,” “aryl,” “heteroaryl,” “aryl C₁-C₆ alkyl”,“heteroaryl C₁-C₆ alkyl,” “aryl C₂-C₆ alkenyl,” “heteroaryl C₂-C₆alkenyl,” “aryl C₂-C₆ alkynyl,” “heteroaryl C₂-C₆ alkynyl,”“C₃-C₈-cycloalkyl C₁-C₆ alkyl,” or “heterocycloalkyl C₁-C₆ alkyl”,including acetyloxy and the like.

The term “acyloxy C₁-C₆ alkyl” refers to C₁-C₆ alkyl groups having anacyloxy substituent, including 2-(ethylcarbonyloxy)ethyl and the like.

The term “alkoxy” refers to the group —O—R where R includes “C₁-C₆alkyl”, “aryl”, “heteroaryl”, “aryl C₁-C₆ alkyl” or “heteroaryl C₁-C₆alkyl”. Preferred alkoxy groups include for example, methoxy, ethoxy,phenoxy and the like.

The term “alkoxy C₁-C₆ alkyl” refers to C₁-C₆ alkyl groups having analkoxy substituent, including methoxyethyl and the like.

The term “alkoxycarbonyl” refers to the group —C(O)OR where R includes“C₁-C₆ alkyl”, “aryl”, “heteroaryl”, “aryl C₁-C₆ alkyl”, “heteroarylC₁-C₆ alkyl” or “heteroalkyl”.

The term “alkoxycarbonyl C₁-C₆ alkyl” refers to C₁-C₆ alkyl groupshaving an alkoxycarbonyl substituent, including2-(benzyloxycarbonyl)ethyl and the like.

The term “aminocarbonyl” refers to the group —C(O)NRR′ where R and R′are independently H, C₁-C₆ alkyl, aryl, heteroaryl, “aryl C₁-C₆ alkyl”or “heteroaryl C₁-C₆ alkyl,” including N-phenyl carbonyl and the like.

The term “aminocarbonyl C₁-C₆ alkyl” refers to alkyl groups having anaminocarbonyl substituent, including 2-(dimethylaminocarbonyl)ethyl,N-ethyl acetamidyl, N,N-Diethyl-acetamidyl and the like.

The term “acylamino” refers to the group —NRC(O)R′ where R and R′ areindependently H, “C₁-C₆ alkyl,” “C₂-C₆ alkenyl,” “C₂-C₆ alkynyl,”“C₃-C₈-cycloalkyl,” “heterocycloalkyl,” “aryl,” “heteroaryl,” “arylC₁-C₆ alkyl”, “heteroaryl C₁-C₆ alkyl,” “aryl C₂-C₆ alkenyl,”“heteroaryl C₂-C₆ alkenyl,” “aryl C₂-C₆ alkynyl,” “heteroaryl C₂-C₆alkynyl,” “cycloalkyl C₁-C₆ alkyl,” or “heterocycloalkyl C₁-C₆ alkyl”,including acetylamino and the like.

The term “acylamino C₁-C₆ alkyl” refers to C₁-C₆ alkyl groups having anacylamino substituent, including 2-(propionylamino)ethyl and the like.

The term “ureido” refers to the group —NRC(O)NR′R″ where R, R′ and R″are independently H, “C₁-C₆ alkyl,” “C₂-C₆ alkenyl,” “alkynyl,”“C₃-C₈-cycloalkyl,” “heterocycloalkyl,” “C₁-C₆ aryl,” “heteroaryl,”“aryl C₁-C₆ alkyl”, “heteroaryl C₁-C₆ alkyl,” “aryl C₂-C₆ alkenyl,”“heteroaryl C₂-C₆ alkenyl,” “aryl C₂-C₆ alkynyl,” “heteroaryl C₂-C₆alkynyl,” “cycloalkyl C₁-C₆ alkyl,” or “heterocycloalkyl C₁-C₆ alkyl,”and where R′ and R,″ together with the nitrogen atom to which they areattached, can optionally form a 3-8-membered heterocycloalkyl ring.

The term “ureido C₁-C₆ alkyl” refers to C₁-C₆ alkyl groups having anureido substituent, including 2-(N′-methylureido)ethyl and the like.

The term “carbamate” refers to the group —NRC(O)OR′ where R and R′ areindependently “C₁-C₆ alkyl,” “C₂-C₆ alkenyl,” “C₂-C₆ alkynyl,”“C₃-C₈-cycloalkyl,” “heterocycloalkyl,” “aryl,” “heteroaryl,” “C₁-C₆alkyl aryl”, “heteroaryl C₁-C₆ alkyl,” “aryl C₂-C₆ alkenyl,” “heteroarylC₂-C₆ alkenyl,” “aryl C₂-C₆ alkynyl,” “heteroaryl C₂-C₆ alkynyl,”“cycloalkyl C₁-C₆ alkyl,” or “heterocycloalkyl C₁-C₆ alkyl” andoptionally R can also be hydrogen.

The term “amino” refers to the group —NRR′ where R and R′ areindependently H, “C₁-C₆ alkyl”, “aryl”, “heteroaryl”, “C₁-C₆ alkylaryl”, “C₁-C₆ alkyl heteroaryl,” “cycloalkyl,” or “heterocycloalkyl,”and where R and R′, together with the nitrogen atom to which they areattached, can optionally form a 3-8-membered heterocycloalkyl ring.

The term “amino alkyl” refers to alkyl groups having an aminosubstituent, including 2-(1-pyrrolidinyl)ethyl and the like.

The term “ammonium” refers to a positively charged group —N⁺RR′R″ whereR, R′ and R″ are independently “C₁-C₆ alkyl”, “C₁-C₆ alkyl aryl”, “C₁-C₆alkyl heteroaryl,” “cycloalkyl,” or “heterocycloalkyl,” and where R andR′, together with the nitrogen atom to which they are attached, canoptionally form a 3-8-membered heterocycloalkyl ring.

The term “ammonium alkyl” refers to alkyl groups having an ammoniumsubstituent, including 1-ethylpyrrolidinium and the like.

The term “halogen” refers to fluoro, chloro, bromo and iodo atoms.

The term “sulfonyloxy” refers to a group —OSO₂—R wherein R is selectedfrom “C₁-C₆ alkyl,” “C₁-C₆ alkyl” substituted with halogens, e.g., an—OSO₂—CF₃ group, “C₂-C₆ alkenyl,” “alkynyl,” “C₃-C₈-cycloalkyl,”“heterocycloalkyl,” “aryl,” “heteroaryl,” “aryl C₁-C₆ alkyl”,“heteroaryl C₁-C₆ alkyl,” “aryl C₂-C₆ alkenyl,” “heteroaryl C₂-C₆alkenyl,” “aryl C₂-C₆ alkynyl,” “heteroaryl C₂-C₆ alkynyl,” “cycloalkylC₁-C₆ alkyl,” or “heterocycloalkyl alkyl”.

The term “sulfonyloxy C₁-C₆ alkyl” refers to alkyl groups having asulfonyloxy substituent, including 2-(methylsulfonyloxy)ethyl and thelike.

The term “sulfonyl” refers to group “—SO₂—R” wherein R is selected from“aryl,” “heteroaryl,” “C₁-C₆ alkyl,” “C₁-C₆ alkyl” substituted withhalogens, e.g., an —SO₂—CF₃ group, “C₂-C₆ alkenyl,” “C₂-C₆ alkynyl,”“C₃-C₈-cycloalkyl,” “heterocycloalkyl,” “aryl,” “heteroaryl,” “arylC₁-C₆ alkyl”, “heteroaryl C₁-C₆ alkyl,” “aryl C₂-C₆ alkenyl,”“heteroaryl C₂-C₆ alkenyl,” “aryl C₂-C₆ alkynyl,” “heteroaryl C₂-C₆alkynyl,” “cycloalkyl C₁-C₆ alkyl,” or “heterocycloalkyl C₁-C₆ alkyl”.

The term “sulfonyl C₁-C₆ alkyl” refers to alkyl groups having a sulfonylsubstituent, including 2-(methylsulfonyl)ethyl and the like.

The term “sulfinyl” refers to a group “—S(O)—R” wherein R is selectedfrom “alkyl,” “alkyl” substituted with halogens, e.g., a —SO—CF₃ group,“C₂-C₆ alkenyl,” “C₂-C₆ alkynyl,” “C₃-C₈-cyclo alkyl,” “hetero cycloalkyl,” “aryl,” “hetero aryl,” “aryl C₁-C₆ alkyl”, “heteroaryl C₁-C₆alkyl,” “aryl C₂-C₆ alkenyl,” “heteroaryl C₂-C₆ alkenyl,” “aryl C₂-C₆alkynyl,” “heteroaryl C₂-C₆ alkynyl,” “C₃-C₈-cycloalkyl C₁-C₆ alkyl,” or“heterocycloalkyl C₁-C₆ alkyl”.

The term “sulfinyl alkyl” refers to alkyl groups having a sulfinylsubstituent, including 2-(methylsulfinyl)ethyl and the like.

The term “sulfanyl” refers to groups —S—R where R includes H, “C₁-C₆alkyl,” “C₁-C₆ alkyl” substituted with halogens, e.g., a —S—CF₃ group,“C₂-C₆ alkenyl,” “C₂-C₆ alkynyl,” “C₃-C₈-cycloalkyl,”“heterocycloalkyl,” “aryl,” “heteroaryl,” “aryl C₁-C₆ alkyl”,“heteroaryl C₁-C₆ alkyl,” “aryl C₂-C₆ alkenyl,” “heteroaryl C₂-C₆alkenyl,” “aryl C₂-C₆ alkynyl,” “alkynylhetero aryl,” “cycloalkyl C₁-C₆alkyl,” or “heterocycloalkyl C₁-C₆ alkyl”. Preferred sulfanyl groupsinclude methylsulfanyl, ethylsulfanyl, and the like.

The term “sulfanyl C₁-C₆ alkyl” refers to C₁-C₅-alkyl groups having asulfanyl substituent, including 2-(ethylsulfanyl)ethyl and the like.

The term “sulfonylamino” refers to a group —NRSO₂—R′ where R and R′ areindependently “C₁-C₆ alkyl,” “C₂-C₆ alkenyl,” “C₂-C₆ alkynyl,”“C₃-C₈-cycloalkyl,” “heterocycloalkyl,” “aryl,” “heteroaryl,” “arylC₁-C₆ alkyl”, “heteroaryl C₁-C₆ alkyl,” “aryl C₂-C₆ alkenyl,”“heteroaryl C₂-C₆ alkenyl,” “aryl C₂-C₆ alkynyl,” “heteroaryl C₂-C₆alkynyl,” “C₃-C₈-cycloalkyl C₁-C₆ alkyl,” or “heterocycloalkyl C₁-C₆alkyl”.

The term “sulfonylamino C₁-C₆ alkyl” refers to alkyl groups having asulfonylamino substituent, including 2-(ethylsulfonylamino)ethyl and thelike.

The term “aminosulfonyl” refers to a group —SO₂—NRR′ where R and R′ areindependently H, “C₁-C₆ alkyl,” “C₂-C₆ alkenyl,” “C₂-C₆ alkynyl,”“C₃-C₈-cycloalkyl,” “heterocycloalkyl,” “aryl,” “heteroaryl,” “arylC₁-C₆ alkyl”, “heteroaryl C₁-C₆ alkyl,” “aryl alkenyl,” “heteroarylC₂-C₆ alkenyl,” “aryl C₂-C₆ alkynyl,” “heteroaryl C₂-C₆ alkynyl,”“C₃-C₈-cycloalkyl C₁-C₆ alkyl,” or “heterocycloalkyl C₁-C₆ alkyl”, andwhere R and R′, together with the nitrogen atom to which they areattached, can optionally form a 3-8-membered heterocycloalkyl ring.Aminosulfonyl groups include cyclohexylaminosulfonyl,piperidinylsulfonyl and the like.

The term “aminosulfonyl C₁-C₆ alkyl” refers to C₁-C₆ alkyl groups havingan aminosulfonyl substituent, including 2-(cyclohexylaminosulfonyl)ethyland the like.

Unless otherwise constrained by the definition of the individualsubstituent, all the above substituents should be understood as beingall optionally substituted.

Unless otherwise constrained by the definition of the individualsubstituent, the term “substituted” refers to groups substituted withfrom 1 to 5 substituents selected from the group consisting of “C₁-C₆alkyl,” “C₂-C₆ alkenyl,” “C₂-C₆ alkynyl,” “C₃-C₈-cycloalkyl,”“heterocycloalkyl,” “C₁-C₆ alkyl aryl,” “C₁-C₆ alkyl heteroaryl,” “C₁-C₆alkyl cycloalkyl,” “C₁-C₆ alkyl heterocycloalkyl,” “amino,”“aminosulfonyl,” “ammonium,” “alkoxy,” “acyl amino,” “amino carbonyl,”“aryl,” “heteroaryl,” “sulfinyl,” “sulfonyl,” “sulphonamide”, “alkoxy,”“alkoxy carbonyl,” “carbamate,” “sulfanyl,” “halogen,” trihalomethyl,cyano, hydroxy, mercapto, nitro, and the like.

The term “pharmaceutically acceptable salts or complexes” refers tosalts or complexes of the below-specified compounds of Formula (I).Examples of such salts include, but are not restricted, to base additionsalts formed by reaction of compounds of Formula (I) with organic orinorganic bases such as hydroxide, carbonate or bicarbonate of a metalcation such as those selected in the group consisting of alkali metals(sodium, potassium or lithium), alkaline earth metals (e.g. calcium ormagnesium), or with an organic primary, secondary or tertiary alkylamine. Amine salts derived from methylamine, dimethylamine,trimethylamine, ethylamine, diethylamine, triethylamine, morpholine,N-Me-D-glucamine, N,N′-bis(phenylmethyl)-1,2-ethanediamine,tromethamine, ethanolamine, diethanolamine, ethylenediamine,N-methylmorpholine, procaine, piperidine, piperazine and the like arecontemplated being within the scope of the instant invention.

Also comprised are salts which are formed from to acid addition saltsformed with inorganic acids (e.g. hydrochloric acid, hydrobromic acid,sulfuric acid, phosphoric acid, nitric acid, and the like), as well assalts formed with organic acids such as acetic acid, oxalic acid,tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid,ascorbic acid, benzoic acid, tannic acid, palmoic acid, alginic acid,polyglutamic acid, naphthalene sulfonic acid, naphthalene disulfonicacid, and poly-galacturonic acid.

“Pharmaceutically active derivative” refers to any compound that uponadministration to the recipient, is capable of providing directly orindirectly, the activity disclosed herein.

The term “indirectly” also encompasses prodrugs which may be convertedto the active form of the drug via endogenous enzymes or metabolism. Theprodrug is a derivative of the compound according to the invention andpresenting NADPH oxidase inhibiting activity that has a chemically ormetabolically decomposable group, and a compound that may be convertedinto a pharmaceutically active compound in vivo by solvolysis underphysiological conditions. The invention further encompasses anytautomers of the compounds according to the invention.

The term “cardiovascular disorder or disease” comprises atherosclerosis,especially diseases or disorders associated with endothelial dysfunctionincluding but not limited to hypertension, cardiovascular complicationsof Type I or Type II diabetes, intimal hyperplasia, coronary heartdisease, cerebral, coronary or arterial vasospasm, endothelialdysfunction, heart failure including congestive heart failure,peripheral artery disease, restenosis, trauma caused by a stent, stroke,ischemic attack, vascular complications such as after organtransplantation, myocardial infarction, hypertension, formation ofatherosclerotic plaques, platelet aggregation, angina pectoris,aneurysm, aortic dissection, ischemic heart disease, cardiachypertrophy, pulmonary embolus, thrombotic events including deep veinthrombosis, injury caused after ischemia by restoration of blood flow oroxygen delivery as in organ transplantation, open heart surgery,angioplasty, hemorrhagic shock, angioplasty of ischemic organs includingheart, brain, liver, kidney, retina and bowel.

The term “respiratory disorder or disease” comprises bronchial asthma,bronchitis, allergic rhinitis, adult respiratory syndrome, cysticfibrosis, lung viral infection (influenza), pulmonary hypertension,idiopathic pulmonary fibrosis and chronic obstructive pulmonary diseases(COPD).

The term “allergic disorder” includes hay fever and asthma.

The term “traumatism” includes polytraumatism.

The term “disease or disorder affecting the metabolism” includesobesity, metabolic syndrome and Type II diabetes.

The term “skin disease” or disorder” includes psoriasis, eczema,dermatitis, wound healing and scar formation.

The term “bone disorder” includes osteoporosis, osteoporasis,osteosclerosis, periodontitis, and hyperparathyroidism.

The term “neurodegenerative disease or disorder” comprises a disease ora state characterized by a central nervous system (CNS) degeneration oralteration, especially at the level of the neurons such as Alzheimer'sdisease, Parkinson's disease, Huntington's disease, amyotrophic lateralsclerosis, epilepsy and muscular dystrophy. It further comprisesneuro-inflammatory and demyelinating states or diseases such asleukoencephalopathies, and leukodystrophies.

The term “demyelinating” is referring to a state or a disease of the CNScomprising the degradation of the myelin around the axons. In thecontext of the invention, the term demyelinating disease is intended tocomprise conditions which comprise a process that demyelinate cells suchas multiple sclerosis, progressive multifocal leukoencephalopathy (PML),myelopathies, any neuroinflammatory condition involving autoreactiveleukocyte within the CNS, congenital metabolic disorder, a neuropathywith abnormal myelination, drug induced demyelination, radiation induceddemyelination, a hereditary demyelinating condition, a prion induceddemyelinating condition, encephalitis induced demyelination or a spinalcord injury. Preferably, the condition is multiple sclerosis.

The term “kidney disease or disorder” includes diabetic nephropathy,renal failure, glomerulonephritis, nephrotoxicity of aminoglycosides andplatinum compounds and hyperactive bladder. In a particular embodiment,the term according to the invention includes chronic kidney diseases ordisorders.

The term “reproduction disorder or disease” includes erectiledysfunction, fertility disorders, prostatic hypertrophy and benignprostatic hypertrophy.

The term “disease or disorder affecting the eye and/or the lens”includes cataract including diabetic cataract, re-opacification of thelens post cataract surgery, diabetic and other forms of retinopathy.

The term “conditions affecting the inner ear” includes presbyacusis,tinnitus, Meniere's disease and other balance problems,utriculolithiasis, vestibular migraine, and noise induced hearing lossand drug induced hearing loss (ototoxicity).

The term “inflammatory disorder or disease” means inflammatory boweldisease, sepsis, septic shock, adult respiratory distress syndrome,pancreatitis, shock induced by trauma, bronchial asthma, allergicrhinitis, rheumatoid arthritis, chronic rheumatoid arthritis,arteriosclerosis, intracerebral hemorrhage, cerebral infarction, heartfailure, myocardial infarction, psoriasis, cystic fibrosis, stroke,acute bronchitis, chronic bronchitis, acute bronchiolitis, chronicbronchiolitis, osteoarthritis, gout, myelitis, ankylosing spondylitis,Reuter syndrome, psoriatic arthritis, spondylarthritis, juvenilearthritis or juvenile ankylosing spondylitis, reactive arthritis,infectious arthritis or arthritis after infection, gonococcal arthritis,syphilitic arthritis, Lyme disease, arthritis induced by “angiitissyndrome,” polyarteritis nodosa, anaphylactic angiitis, Luegenecgranulomatosis, rheumatoid polymyalgia, articular cell rheumatism,calcium crystal deposition arthritis, pseudogout, non-arthriticrheumatism, bursitis, tendosynovitis, epicondyle inflammation (tenniselbow), carpal tunnel syndrome, disorders by repetitive use (typing),mixed form of arthritis, neuropathic arthropathy, hemorrhagic arthritis,vascular peliosis, hypertrophic osteoarthropathy, multicentricreticulohistiocytosis, arthritis induced by specific diseases, bloodpigmentation, sickle cell disease and other hemoglobin abnormality,hyperlipoproteinemia, dysgammaglobulinemia, hyperparathyroidism,acromegaly, familial Mediterranean fever, Bechet's disease, systemicautoimmune disease erythematosus, multiple sclerosis and Crohn's diseaseor diseases like relapsing polychondritis, chronic inflammatory boweldiseases (IBD) or the related diseases which require the administrationto a mammal in a therapeutic effective dose of a compound expressed byFormula (I) in a sufficient dose to inhibit NADPH oxidase.

The term “liver diseases or disorders” include liver fibrosis, alcoholinduced fibrosis, steatosis and non alcoholic steatohepatitis.

The term “arthritis” means acute rheumatic arthritis, chronic rheumatoidarthritis, chlamydial arthritis, chronic absorptive arthritis, chylousarthritis, arthritis based on bowel disease, filarial arthritis,gonorrheal arthritis, gouty arthritis, hemophilic arthritis,hypertrophic arthritis, juvenile chronic arthritis, Lyme arthritis,neonatal foal arthritis, nodular arthritis, ochronotic arthritis,psoriatic arthritis or suppurative arthritis, or the related diseaseswhich require the administration to a mammal in a therapeutic effectivedose of a compound expressed by Formula (I) in a sufficient dose toinhibit NADPH oxidase.

The term “pain” includes hyperalgesia associated with inflammatory pain.

The term “cancer” means carcinoma (e.g., fibrosarcoma, myxosarcoma,liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma,endothelium sarcoma, lymphangiosarcoma, lymphangioendothelioma,periosteoma, mesothelioma, Ewing's tumor, leiomyosarcoma,rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer,ovarian cancer, renal cancer, prostatic carcinoma, squamous cellcarcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma,sebaceous gland carcinoma, papillary carcinoma, papillaryadenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogeniccarcinoma, renal cell carcinoma, hepatocellular carcinoma,cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma,Wilms' tumor, cervical cancer, orchioncus, lung cancer, small-cell lungcancer, lung adenocarcinoma, bladder cancer or epithelial cancer) or therelated diseases which require the administration to a mammal in atherapeutic effective dose of a compound expressed by the Formula (I) ina sufficient dose to inhibit NADPH oxidase.

The term “disease or disorders of the gastrointestinal system”, includesgastric mucosa disorders ischemic bowel disease management,enteritis/colitis, cancer chemotherapy, or neutropenia.

The term “angiogenesis” includes sprouting angiogenesis, intussusceptiveangiogenesis, vasculogenesis, arteriogenesis and lymphangiogenesis.Angiogenesis is the formation of new blood vessels from pre-existingcapillaries or post-capillary venules and occurs in pathologicalconditions such as cancers, arthritis and inflammation. A large varietyof tissues, or organs comprised of organized tissues, can supportangiogenesis in disease conditions including skin, muscle, gut,connective tissue, joints, bones and the like tissue in which bloodvessels can invade upon angiogenic stimuli. As used herein, the term“angiogenesis-dependent condition” is intended to mean a condition wherethe process of angiogenesis or vasculogenesis sustains or augments apathological condition. Vasculogenesis results from the formation of newblood vessels arising from angioblasts which are endothelial cellprecursors. Both processes result in new blood vessel formation and areincluded in the meaning of the term angiogenesis-dependent conditions.Similarly, the term “angiogenesis” as used herein is intended to includede novo formation of vessels such as those arising from vasculogenesisas well as those arising from branching and sprouting of existingvessels, capillaries and venules.

The term “angiogenesis inhibitory,” means which is effective in thedecrease in the extent, amount, or rate of neovascularization. Effectinga decrease in the extent, amount, or rate of endothelial cellproliferation or migration in the tissue is a specific example ofinhibiting angiogenesis. Angiogenesis inhibitory activity isparticularly useful in the treatment of any cancers as it targets tumorgrowth process and in the absence of neovascularization of tumor tissue,the tumor tissue does not obtain the required nutrients, slows ingrowth, ceases additional growth, regresses and ultimately becomesnecrotic resulting in killing of the tumor. Further, an angiogenesisinhibitory activity is particularly useful in the treatment of anycancers as it is particularly effective against the formation ofmetastases because their formation also requires vascularization of aprimary tumor so that the metastatic cancer cells can exit the primarytumor and their establishment in a secondary site requiresneovascularization to support growth of the metastases.

As used herein, “treatment” and “treating” and the like generally meanobtaining a desired pharmacological and physiological effect. The effectmay be prophylactic in terms of preventing or partially preventing adisease, symptom or condition thereof and/or may be therapeutic in termsof a partial or complete cure of a disease, condition, symptom oradverse effect attributed to the disease. The term “treatment” as usedherein covers any treatment of a disease in a mammal, particularly ahuman, and includes: (a) preventing the disease from occurring in asubject which may be predisposed to the disease but has not yet beendiagnosed as having it; (b) inhibiting the disease, i.e., arresting itsdevelopment; or relieving the disease, i.e., causing regression of thedisease and/or its symptoms or conditions.

The term “subject” as used herein refers to mammals. For examples,mammals contemplated by the present invention include human, primates,domesticated animals such as cattle, sheep, pigs, horses and the like.

The term “inhibitor” used in the context of the invention is defined asa molecule that inhibits completely or partially the activity of NADPHoxidase and/or inhibit or reduce the generation of reactive oxygenspecies (ROS).

Compounds According to the Invention

In one embodiment, the invention provides a pyrazolo piperidinederivative according to Formula (I):

wherein R¹ is selected from H; optionally substituted alkoxycarbonyl;optionally substituted C₁-C₆ alkyl such as optionally substituted methyl(e.g. methyl), optionally substituted ethyl (e.g. 2-hydroxy ethyl),optionally substituted propyl (e.g. 3-propane nitrile); optionallysubstituted C₂-C₆ alkenyl; optionally substituted C₂-C₆ alkynyl;optionally substituted alkoxy; optionally substituted alkoxy C₁-C₆ alkylsuch as optionally substituted optionally substituted alkoxy ethyl likeoptionally substituted phenoxy ethyl (e.g. phenoxy ethyl,4-chlorophenoxy ethyl), optionally substituted methoxy ethyl (e.g.2-methoxy ethyl); optionally substituted aminoalkyl such as optionallysubstituted amino ethyl (e.g. 2-dimethylamino ethyl); optionallysubstituted acyl; optionally substituted aryl such as optionallysubstituted phenyl (e.g. phenyl, 2-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 1-methoxy phenyl, 1-chlorophenyl, 2-chlorophenyl,4-chlorophenyl, 3-chlorophenyl, 4-chloro-2-fluorophenyl, 2-fluorophenyl,3-fluorophenyl, 2-chloro-4-fluorophenyl, 3-phenyl acetamide, 3-benzyloxyphenyl, 4-benzonitrile, 3-benzonitrile, 4-trifluoromethyl phenyl,2-fluoro-4-methyl sulfonyl phenyl); optionally substituted C₁-C₆ alkylaryl; optionally substituted aryl C₁-C₆ alkyl such as optionallysubstituted aryl methyl such as optionally substituted phenyl methyl(e.g. benzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-methoxy benzyl,3-methoxy benzyl, 4-methoxybenzyl, 3-hydroxy benzyl,2-chloro-4-fluorobenzyl, 2-dimethylamino benzyl, 2-diphenyl methyl),optionally substituted phenyl ethyl (e.g. 1-phenyl ethyl, 2-phenylethyl); optionally substituted heteroaryl such as optionally substitutedbenzodioxolyl (e.g. 1,3 benzodioxol-5-yl), optionally substitutedbenzothiazolyl (e.g. 2-methyl 1,3-benzothiazol-6-yl), optionallysubstituted [1,2,4]triazolo[4,3-b]pyridazinyl (e.g.[1,2,4]triazolo[4,3-b]pyridazin-6-yl), optionally substituted pyridinyl(e.g. pyridine-2-yl, [(4-methylpiperazin-1-yl)sulfonyl]pyridine-2-yl,4-methyl piperazin-1-yl sulfonyl pyridine-2-yl), optionally substituted2,3-dihydro-1,4-benzodioxin-6-yl (e.g. 2,3-dihydro-1,4-benzodioxinyl),optionally substituted quinoxalinyl (e.g. 2-quinoxalin-2-yl), optionallysubstituted quinolinyl (e.g. 7-chloroquinolin-4-yl); optionallysubstituted C₁-C₆ alkyl heteroaryl; optionally substituted heteroarylC₁-C₆ alkyl such as optionally substituted pyridine C₁-C₆ alkyl likeoptionally substituted pyridine methyl (e.g. 2-pyridin-3-ylmethyl),optionally substituted imidazo[1,2-a]pyridine-2-yl methyl (e.g.imidazo[1,2-a]pyridine-2-yl methyl); optionally substituted C₂-C₆alkenyl aryl; optionally substituted aryl C₂-C₆ alkenyl; optionallysubstituted C₂-C₆ alkenyl heteroaryl; optionally substituted heteroarylC₂-C₆ alkenyl; optionally substituted C₃-C₈-cycloalkyl; optionallysubstituted heterocycloalkyl such as optionally substituted piperidine(e.g. 1-methyl piperidin-4-yl, 1-benzyl piperidin-4yl); optionallysubstituted C₁-C₆ alkyl C₃-C₈-cycloalkyl; optionally substitutedC₃-C₈-cycloalkyl C₁-C₆ alkyl; optionally substituted C₁-C₆ alkylheterocycloalkyl and optionally substituted heterocycloalkyl C₁-C₆ alkylsuch as optionally substituted heterocycloalkyl ethyl like morpholinylethyl (e.g. 2-morpholin-4-ylethyl) or piperidinyl ethyl (e.g.2-piperidin-1-ylethyl); R² is selected from H; optionally substitutedC₁-C₆ alkyl; optionally substituted C₂-C₆ alkenyl; optionallysubstituted C₂-C₆ alkynyl; optionally substituted aryl; optionallysubstituted heteroaryl; optionally substituted C₃-C₈-cycloalkyl;optionally substituted heterocycloalkyl; optionally substitutedC₃-C₈-cycloalkyl C₁-C₆ alkyl; optionally substituted heterocycloalkylC₁-C₆ alkyl; optionally substituted aryl C₁-C₆ alkyl and optionallysubstituted heteroaryl C₁-C₆ alkyl; R³ is selected from —S(O)—R⁴,—S(O)₂—R⁴, optionally substituted C₃-C₈-cycloalkyl, optionallysubstituted heterocycloalkyl and —CR⁵R⁶R⁷; R⁴ is selected from H;optionally substituted amino; optionally substituted C₁-C₆ alkyl such asoptionally substituted methyl (e.g. methyl); optionally substitutedC₂-C₆ alkenyl; optionally substituted C₂-C₆ alkynyl; optionallysubstituted alkoxy; optionally substituted alkoxy C₁-C₆ alkyl suchoptionally substituted aminoalkyl; optionally substituted acyl;optionally substituted aryl such as optionally substituted phenyl (e.g.phenyl, 4-methyl phenyl, 3-benzonitrile, 3-fluoro phenyl, 3-methoxyphenyl, 3-chlorophenyl, 4-chlorophenyl, 4-methoxy phenyl,3-chloro-4-fluoro phenyl, 4-dichloro phenyl, biphenyl, 3-trifluoromethylphenyl, 4-tert-butyl phenyl); optionally substituted C₁-C₆ alkyl aryl;optionally substituted aryl C₁-C₆ alkyl such as optionally substitutedaryl methyl; optionally substituted heteroaryl such as optionallysubstituted pyridine (e.g. pyridine-3-yl), optionally substitutedbenzoxazinyl (e.g. 1,4-benzoxazin-6-yl), optionally substitutedquinolinyl (e.g. quinolin-8-yl); optionally substituted C₁-C₆ alkylheteroaryl; optionally substituted heteroaryl C₁-C₆ alkyl; optionallysubstituted C₂-C₆ alkenyl aryl; optionally substituted aryl C₂-C₆alkenyl; optionally substituted C₂-C₆ alkenyl heteroaryl; optionallysubstituted heteroaryl C₂-C₆ alkenyl; optionally substitutedC₃-C₈-cycloalkyl; optionally substituted heterocycloalkyl; optionallysubstituted C₁-C₆ alkyl C₃-C₈-cycloalkyl; optionally substitutedC₃-C₈-cycloalkyl C₁-C₆ alkyl; optionally substituted C₁-C₆ alkylheterocycloalkyl and optionally substituted heterocycloalkyl C₁-C₆alkyl; R⁵ is selected from H and —CR⁸R⁹R¹⁰; R⁶ is selected from H and—CR¹¹R¹²R¹³; R⁷ is selected from H, —CR¹⁴R¹⁵R¹⁶ and —C(O)—R¹⁷; R⁸, R⁹,R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, and R¹⁷ are independently selected from H;halogen; optionally substituted amino (e.g. methyl amino); optionallysubstituted acyl; optionally substituted C₁-C₆ alkyl such as optionallysubstituted methyl (e.g. methyl); optionally substituted C₂-C₆ alkenyl;optionally substituted C₂-C₆ alkynyl; optionally substituted aryl;optionally substituted C₁-C₆ alkyl aryl; optionally substituted arylC₁-C₆ alkyl; optionally substituted heteroaryl; optionally substitutedC₁-C₆ alkyl heteroaryl; optionally substituted heteroaryl C₁-C₆ alkyl;optionally substituted C₂-C₆ alkenyl aryl; optionally substituted arylC₂-C₆ alkenyl; optionally substituted C₂-C₆ alkenyl heteroaryl;optionally substituted heteroaryl C₂-C₆ alkenyl; optionally substitutedC₃-C₈-cycloalkyl; optionally substituted heterocycloalkyl; optionallysubstituted C₁-C₆ alkyl C₃-C₈-cycloalkyl; optionally substitutedC₃-C₈-cycloalkyl C₁-C₆ alkyl; optionally substituted C₁-C₆ alkylheterocycloalkyl and optionally substituted heterocycloalkyl C₁-C₆alkyl; —CR⁸R⁹R¹⁰, —CR¹¹R¹²R¹³ or —CR¹⁴R¹⁵R¹⁶ can independently form anoptionally substituted ring selected from an optionally substituted arylsuch as optionally substituted phenyl (e.g. phenyl, 4-cyano phenyl,4-chlorophenyl, 1-chlorophenyl, 2-chlorophenyl, 3-chlorophenyl,3-chloro-4-fluorophenyl, 2-methoxy phenyl, 4-methoxyphenyl,3-methoxyphenyl, 2,4-dichlorophenyl, 3,3-dichlorophenyl,3,3-dimethoxyphenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl,3-trifluoromethyl phenyl, 2-cyano phenyl, 3-benzonitrile, 4-methylsulfonyl phenyl, 3,5-dimethoxy phenyl, 4-phenyl acetamide,2-nitro-4-fluorophenyl); an optionally substituted heteroaryl such asoptionally substituted pyridine (e.g. pyridine-2-yl, pyridine-3-yl,6-chloropyridin-3-yl), optionally substituted thiazolyl (e.g.1,3-thiazol-4-yl), optionally substituted pyrazolyl (e.g.1-methyl-1H-pyrazol-3-yl), optionally substituted benzimidazolyl (e.g.1H-benzymidazol-2-yl), optionally substituted quinolinyl (e.g.quinolinyl-2yl) optionally substituted isoxazolyl (e.g. isoxazol-3-yl),optionally substituted benzothiazolyl (e.g. 1,3-benzothiazol-2-yl); anoptionally substituted C₃-C₈-cycloalkyl or an optionally substitutedheterocycloalkyl; as well as tautomers, geometrical isomers, opticallyactive forms, pharmaceutically acceptable salts and pharmaceuticallyactive derivative thereof, with the proviso that the compound is notselected from the group consisting of:

-   6-methyl-2-phenyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   6-benzyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one    (RN=909187-64-0); and-   6-benzyl-2,3a,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one    (RN=62458-89-3).

In a particular embodiment, the invention provides a tautomer ofcompound according to Formula (I), selected from a compound of Formula(Ia) and a compound of Formula (Ib):

as well as optically active forms, pharmaceutically acceptable salts andpharmaceutically active derivative thereof, wherein R¹, R², R³, R⁴, R⁵,R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are as definedin the detailed description.Compositions

The invention provides pharmaceutical or therapeutic agents ascompositions and methods for treating a patient, preferably a mammalianpatient, and most preferably a human patient who is suffering from amedical disorder, and in particular a disorder mediated by NADPHoxidase, such as a cardiovascular disorder or disease, a respiratorydisorder or disease, a disease or disorder affecting the metabolism, askin disorder, a bone disorder, a neuroinflammatory disorder, aneurodegenerative disorder, a kidney disease, a reproduction disorder, adisease or disorder affecting the eye and/or the lens, a conditionaffecting the inner ear, an inflammatory disorder or disease, a liverdisease, pain, a cancer, angiogenesis, angiogenesis-dependent conditionsand/or a disease or disorders of the gastrointestinal system.

Pharmaceutical compositions of the invention can contain one or morepyrazolo piperidine derivative in any form described herein.Compositions of this invention may further comprise one or morepharmaceutically acceptable additional ingredient(s), such as alum,stabilizers, antimicrobial agents, buffers, coloring agents, flavoringagents, adjuvants, and the like.

The compounds of the invention, together with a conventionally employedadjuvant, carrier, diluent or excipient may be placed into the form ofpharmaceutical compositions and unit dosages thereof, and in such formmay be employed as solids, such as tablets or filled capsules, orliquids such as solutions, suspensions, emulsions, elixirs, or capsulesfilled with the same, all for oral use, or in the form of sterileinjectable solutions for parenteral (including subcutaneous) use. Suchpharmaceutical compositions and unit dosage forms thereof may compriseingredients in conventional proportions, with or without additionalactive compounds or principles, and such unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed. Compositions accordingto the invention are preferably injectable.

Compositions of this invention may also be liquid formulations,including, but not limited to, aqueous or oily suspensions, solutions,emulsions, syrups, and elixirs. Liquid forms suitable for oraladministration may include a suitable aqueous or non-aqueous vehiclewith buffers, suspending and dispensing agents, colorants, flavors andthe like. The compositions may also be formulated as a dry product forreconstitution with water or other suitable vehicle before use. Suchliquid preparations may contain additives, including, but not limitedto, suspending agents, emulsifying agents, non-aqueous vehicles andpreservatives. Suspending agents include, but are not limited to,sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin,hydroxyethylcellulose, carboxymethyl cellulose, aluminum stearate gel,and hydrogenated edible fats. Emulsifying agents include, but are notlimited to, lecithin, sorbitan monooleate, and acacia. Nonaqueousvehicles include, but are not limited to, edible oils, almond oil,fractionated coconut oil, oily esters, propylene glycol, and ethylalcohol. Preservatives include, but are not limited to, methyl or propylp-hydroxybenzoate and sorbic acid. Further materials as well asprocessing techniques and the like are set out in Part 5 of Remington'sPharmaceutical Sciences, 21^(st) Edition, 2005, University of theSciences in Philadelphia, Lippincott Williams & Wilkins, which isincorporated herein by reference.

Solid compositions of this invention may be in the form of tablets orlozenges formulated in a conventional manner. For example, tablets andcapsules for oral administration may contain conventional excipientsincluding, but not limited to, binding agents, fillers, lubricants,disintegrants and wetting agents. Binding agents include, but are notlimited to, syrup, acacia, gelatin, sorbitol, tragacanth, mucilage ofstarch and polyvinylpyrrolidone. Fillers include, but are not limitedto, lactose, sugar, microcrystalline cellulose, maize starch, calciumphosphate, and sorbitol. Lubricants include, but are not limited to,magnesium stearate, stearic acid, talc, polyethylene glycol, and silica.Disintegrants include, but are not limited to, potato starch and sodiumstarch glycollate. Wetting agents include, but are not limited to,sodium lauryl sulfate. Tablets may be coated according to methods wellknown in the art.

Injectable compositions are typically based upon injectable sterilesaline or phosphate-buffered saline or other injectable carriers knownin the art.

Compositions of this invention may also be formulated as suppositories,which may contain suppository bases including, but not limited to, cocoabutter or glycerides. Compositions of this invention may also beformulated for inhalation, which may be in a form including, but notlimited to, a solution, suspension, or emulsion that may be administeredas a dry powder or in the form of an aerosol using a propellant, such asdichlorodifluoromethane or trichlorofluoromethane. Compositions of thisinvention may also be formulated transdermal formulations comprisingaqueous or non-aqueous vehicles including, but not limited to, creams,ointments, lotions, pastes, medicated plaster, patch, or membrane.

Compositions of this invention may also be formulated for parenteraladministration, including, but not limited to, by injection orcontinuous infusion. Formulations for injection may be in the form ofsuspensions, solutions, or emulsions in oily or aqueous vehicles, andmay contain formulation agents including, but not limited to,suspending, stabilizing, and dispersing agents. The composition may alsobe provided in a powder form for reconstitution with a suitable vehicleincluding, but not limited to, sterile, pyrogen-free water.

Compositions of this invention may also be formulated as a depotpreparation, which may be administered by implantation or byintramuscular injection. The compositions may be formulated withsuitable polymeric or hydrophobic materials (as an emulsion in anacceptable oil, for example), ion exchange resins, or as sparinglysoluble derivatives (as a sparingly soluble salt, for example).

Compositions of this invention may also be formulated as a liposomepreparation. The liposome preparation can comprise liposomes whichpenetrate the cells of interest or the stratum corneum, and fuse withthe cell membrane, resulting in delivery of the contents of the liposomeinto the cell. Other suitable formulations can employ niosomes. Niosomesare lipid vesicles similar to liposomes, with membranes consistinglargely of non-ionic lipids, some forms of which are effective fortransporting compounds across the stratum corneum. The compounds of thisinvention can also be administered in sustained release forms or fromsustained release drug delivery systems. A description of representativesustained release materials can also be found in the incorporatedmaterials in Remington's Pharmaceutical Sciences.

Mode of Administration

Compositions of this invention may be administered in any manner,including, but not limited to, orally, parenterally, sublingually,transdermally, rectally, transmucosally, topically, via inhalation, viabuccal or intranasal administration, or combinations thereof. Parenteraladministration includes, but is not limited to, intravenous,intra-arterial, intra-peritoneal, subcutaneous, intramuscular,intra-thecal, and intra-articular. The compositions of this inventionmay also be administered in the form of an implant, which allows slowrelease of the compositions as well as a slow controlled i.v. infusion.In a preferred embodiment, pyrazolo piperidine derivatives according tothe invention are administered intravenously or subcutaneously.

This invention is further illustrated by the following examples that arenot intended to limit the scope of the invention in any way.

The dosage administered, as single or multiple doses, to an individualwill vary depending upon a variety of factors, including pharmacokineticproperties, patient conditions and characteristics (sex, age, bodyweight, health, size), extent of symptoms, concurrent treatments,frequency of treatment and the effect desired.

Combination

According to one embodiment of the invention, the compounds according tothe invention and pharmaceutical formulations thereof can beadministered alone or in combination with a co-agent useful in thetreatment of cancer, such as substances used in conventionalchemotherapy directed against solid tumors and for control ofestablishment of metastases or substances used in hormonotherapy or anyother molecule that act by triggering programmed cell death e.g. forexample a co-agent selected from the category of drugs that stop thesynthesis of pre DNA molecule building blocks such as methotrexate(Abitrexate®), fluorouracil (Adrucil®), hydroxyurea (Hydrea®), andmercaptopurine (Purinethol®). e.g. for example a co-agent selected fromthe category of drugs that directly damage the DNA in the nucleus of thecell such as cisplatin (Platinol®) and antibiotics—daunorubicin(Cerubidine®), doxorubicin (Adriamycin®), and etoposide (VePesid®). e.g.for example a co-agent selected from the category of drugs that effectthe synthesis or breakdown of the mitotic spindles such as Vinblastine(Velban®), Vincristine (Oncovin®) and Pacitaxel (Taxol®).

According to another embodiment of the invention, the compoundsaccording to the invention and pharmaceutical formulations thereof canbe administered in combination with agents targeting cell-surfaceproteins such as gene transfer of cytokine receptor chain andreceptor-targeted cytotoxin administration

According to another embodiment of the invention, the compoundsaccording to the invention and pharmaceutical formulations thereof canbe administered in combination with radiation therapy.

The invention encompasses the administration of a compound according tothe invention or of a pharmaceutical formulation thereof, wherein thecompound according to the invention or the pharmaceutical formulationthereof is administered to an individual prior to, simultaneously orsequentially with other therapeutic regimens or co-agents useful in thetreatment of cancers (e.g. multiple drug regimens), in a therapeuticallyeffective amount. Compounds according to the invention or thepharmaceutical formulations thereof that are administered simultaneouslywith said co-agents can be administered in the same or differentcomposition(s) and by the same or different route(s) of administration.

In another particular embodiment, the compounds and methods of theinvention are contemplated for use in the treatment of cancers whereinthe administration of a compound according to the invention is typicallyconducted during or after chemotherapy, hormonotherapy or radiotherapy.

In another particular embodiment, the compounds and methods of theinvention are contemplated for use in the treatment of cancers whereinthe administration of a compound according to the invention is typicallyconducted after a regimen of chemotherapy, hormonotherapy orradiotherapy at times where the tumor tissue will be responding to thetoxic assault by inducing angiogenesis to recover by the provision of ablood supply and nutrients to the tumor tissue.

In another embodiment, the administration of a compound according to theinvention is performed after surgery where solid tumors have beenremoved as a prophylaxis against metastases.

Patients

In an embodiment, patients according to the invention are patientssuffering from a cardiovascular disorder or disease.

In another embodiment, patients according to the invention are patientssuffering from a respiratory disorder or disease.

In another embodiment, patients according to the invention are patientssuffering from a disease or disorder affecting the metabolism.

In another embodiment, patients according to the invention are patientssuffering from a skin disorder.

In another embodiment, patients according to the invention are patientssuffering from a bone disorder.

In another embodiment, patients according to the invention are patientssuffering from a neuroinflammatory disorder and/or a neurodegenerativedisorder.

In another embodiment, patients according to the invention are patientssuffering from a kidney disease.

In another embodiment, patients according to the invention are patientssuffering from a reproduction disorder.

In another embodiment, patients according to the invention are patientssuffering from a disease or disorder affecting the eye and/or the lensand/or a condition affecting the inner ear.

In another embodiment, patients according to the invention are patientssuffering from an inflammatory disorder or disease.

In another embodiment, patients according to the invention are patientssuffering from a liver disease.

In another embodiment, patients according to the invention are patientssuffering from pain, such as inflammatory pain.

In another embodiment, patients according to the invention are patientssuffering from a cancer.

In another embodiment, patients according to the invention are sufferingfrom angiogenesis or an angiogenesis-dependent condition.

In another embodiment, patients according to the invention are patientssuffering from allergic disorders.

In another embodiment, patients according to the invention are patientssuffering from traumatisms.

In another embodiment, patients according to the invention are patientssuffering from septic, hemorrhagic and anaphylactic shock.

In another embodiment, patients according to the invention are patientssuffering from a disease or disorders of the gastrointestinal system.

Use According to the Invention

In another embodiment, the invention provides a pyrazolo piperidinederivative according to Formula (I) wherein R¹ is H; R², R³, R⁴, R⁵, R⁶,R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are as defined inthe detailed description; as well as pharmaceutically acceptable saltsand pharmaceutically active derivative thereof for use as a medicament.

In a further particular embodiment, is provided a pyrazolo piperidinederivative according to Formula (I) wherein R¹ is H; R², R³, R⁴, R⁵, R⁶,R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are as defined inthe detailed description for use as a medicament with the proviso thatthe compound is not6-benzyl-2,3a,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one(RN=62458-89-3).

In another further particular embodiment, is provided a pyrazolopiperidine derivative according to Formula (I) wherein R¹ is H; R², R³,R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are asdefined in the detailed description for use as a medicament with theproviso that the compound is not6-methyl-2-phenyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one.

In another further embodiment, the invention provides a pyrazolopiperidine derivative according to the invention wherein R¹ is H; R²,R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷are as defined in the detailed description.

In a further embodiment, the invention provides a pyrazolo piperidinederivative according to the invention wherein R¹ is selected fromoptionally substituted aryl and optionally substituted hetero aryl; R²,R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷are as defined in the detailed description.

In another further embodiment, the invention provides a pyrazolopiperidine derivative according to the invention wherein R¹ is selectedfrom optionally substituted C₁-C₆ alkyl; optionally substituted C₂-C₆alkenyl; optionally substituted C₂-C₆ alkynyl; R², R³, R⁴, R⁵, R⁶, R⁷,R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are as defined in thedetailed description.

In another further embodiment, the invention provides a pyrazolopiperidine derivative according to the invention wherein R¹ is selectedfrom optionally substituted aryl C₁-C₆ alkyl and optionally substitutedheteroaryl C₁-C₆ alkyl; R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹²,R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are as defined in the detailed description.

In another further embodiment, the invention provides a pyrazolopiperidine derivative according to the invention wherein R¹ isoptionally substituted heterocycloalkyl; R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹,R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are as defined in the detaileddescription.

In another further embodiment, the invention provides a pyrazolopiperidine derivative according to the invention wherein R¹ isoptionally substituted heterocycloalkyl C₁-C₆ alkyl; R², R³, R⁴, R⁵, R⁶,R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are as defined inthe detailed description.

In another further embodiment, the invention provides a pyrazolopiperidine derivative according to the invention wherein R¹ isoptionally substituted alkoxy C₁-C₆ alkyl; R², R³, R⁴, R⁵, R⁶, R⁷, R⁸,R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are as defined in thedetailed description.

In another further embodiment, the invention provides a pyrazolopiperidine derivative according to the invention wherein R¹ isoptionally substituted aminoalkyl; R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰,R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are as defined in the detaileddescription.

In another further embodiment, the invention provides a pyrazolopiperidine derivative according to the invention wherein R² is H; R¹,R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷are as defined in the detailed description.

In another further embodiment, the invention provides a pyrazolopiperidine derivative according to the invention wherein R³ is —CR⁵R⁶R⁷;R¹, R², R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷are as defined in the detailed description.

In another further embodiment, the invention provides a pyrazolopiperidine derivative according to the invention wherein R³ is —CR⁵R⁶R⁷;R⁵ and R⁶ are independently selected from H and optionally substitutedC₁-C₆ alkyl; R⁷ is —CR¹⁴R¹⁵R¹⁶; R¹, R², R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are asdefined in the detailed description.

In another further embodiment, the invention provides a pyrazolopiperidine derivative according to the invention wherein R³ is —CR⁵R⁶R⁷;R⁵ and R⁶ are independently selected from H and optionally substitutedC₁-C₆ alkyl; R⁷ is CR¹⁴R¹⁵R¹⁶; —CR¹⁴R¹⁵R¹⁶ form a ring selected fromoptionally substituted aryl and optionally substituted heteroaryl; R¹and R² are as defined in the detailed description.

In another further embodiment, the invention provides a pyrazolopiperidine derivative according to the invention wherein R³ is —CR⁵R⁶R⁷;R⁵ and R⁶ are independently selected from H and optionally substitutedC₁-C₆ alkyl; R⁷ is —C(O)R¹⁷; R¹, R² and R¹⁷ are as defined in thedetailed description.

In another embodiment, the invention provides a pyrazolo piperidinederivative according to the invention wherein R³ is S(O)₂—R⁴; R¹, R² andR⁴ are as defined in the detailed description.

In another further embodiment, the invention provides a pyrazolopiperidine derivative according to the invention wherein R³ is S(O)₂—R⁴and R⁴ is selected from optionally substituted C₁-C₆ alkyl; optionallysubstituted C₂-C₆ alkenyl and optionally substituted C₂-C₆ alkynyl; R¹and R² are as defined in the detailed description.

In another further embodiment, the invention provides a pyrazolopiperidine derivative according to the invention wherein R³ is S(O)₂—R⁴and R⁴ is selected from optionally substituted aryl and optionallysubstituted heteroaryl; R¹ and R² are as defined in the detaileddescription.

In another embodiment, the invention provides a use of a pyrazolopiperidine derivative according to Formula (I) wherein R¹, R², R³, R⁴,R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are asdefined in the detailed description, as well as tautomers, geometricalisomers, optically active forms, pharmaceutically acceptable salts andpharmaceutically active derivative thereof for the preparation of apharmaceutical composition for the treatment or prophylaxis of a diseaseor condition selected from cardiovascular disorders, respiratorydisorders, metabolism disorders, skin disorders, bone disorders,neuroinflammatory and/or neurodegenerative disorders, kidney diseases,reproduction disorders, diseases affecting the eye and/or the lensand/or conditions affecting the inner ear, inflammatory disorders, liverdiseases, pain, cancers, allergic disorders, traumatisms, septic,hemorrhagic and anaphylactic shock, disorders of the gastrointestinalsystem, angiogenesis, angiogenesis-dependent conditions and otherdiseases and disorders associated with Nicotinamide adenine dinucleotidephosphate oxidase (NADPH Oxidase).

In another embodiment, the invention provides a pyrazolo piperidinederivative according to Formula (I) wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷,R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are as defined in thedetailed description, as well as tautomers, geometrical isomers,optically active forms, pharmaceutically acceptable salts andpharmaceutically active derivative thereof for the treatment orprophylaxis of a disease or condition selected from cardiovasculardisorders, respiratory disorders, metabolism disorders, skin disorders,bone disorders, neuroinflammatory and/or neurodegenerative disorders,kidney diseases, reproduction disorders, diseases affecting the eyeand/or the lens and/or conditions affecting the inner ear, inflammatorydisorders, liver diseases, pain, cancers, allergic disorders,traumatisms, septic, hemorrhagic and anaphylactic shock, disorders ofthe gastrointestinal system, angiogenesis, angiogenesis-dependentconditions and other diseases and disorders associated with Nicotinamideadenine dinucleotide phosphate oxidase (NADPH Oxidase).

Compounds of the present invention include in particular those selectedfrom the following group:

-   6-benzyl-2-(2-chloro-4-fluorophenyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   6-benzyl-2-[3-(benzyloxy)phenyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   6-benzyl-2-(4-chlorobenzyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   6-benzyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   2,6-dibenzyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   6-benzyl-2-(3-methoxyphenyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   6-benzyl-2-(3-chlorophenyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   6-benzyl-2-phenyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;    6-benzyl-2-methyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   6-(3-chlorobenzyl)-2-(3-methoxyphenyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   6-(3,5-dimethoxybenzyl)-2-(3-methoxyphenyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   6-benzyl-2-(2-methoxyphenyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   6-(4-chlorobenzyl)-2-(3-methoxyphenyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   6-(2,4-dichlorobenzyl)-2-(3-methoxyphenyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   2-benzyl-6-(3-chlorobenzyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   6-(3-chlorobenzyl)-2-(2-hydroxyethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   6-(3-chlorobenzyl)-2-(3-methoxybenzyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   6-(3-chlorobenzyl)-2-(2-methoxybenzyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   6-(3-chlorobenzyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   6-(3-chlorobenzyl)-2-(1-methylpiperidin-4-yl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   2-benzyl-6-(4-chlorobenzyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one-   6-(4-chlorobenzyl)-2-(2-methoxybenzyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   6-(4-chlorobenzyl)-2-(3-methoxybenzyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   6-(4-chlorobenzyl)-2-(2-hydroxyethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   2-(3-methoxyphenyl)-6-(1-phenylethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   6-(3-chlorobenzyl)-2-(2-methoxyethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   6-(4-chlorobenzyl)-2-(2-methoxyethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   2-(1,3-benzodioxol-5-yl)-6-(4-chlorobenzyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   2-(1,3-benzodioxol-5-yl)-6-(3-chlorobenzyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   4-[6-(3-chlorobenzyl)-3-oxo-1,3,4,5,6,7-hexahydro-2H-pyrazolo[3,4-c]pyridin-2-yl]benzonitrile;-   6-(3-chlorobenzyl)-2-(4-chlorophenyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   6-(3-chlorobenzyl)-2-(2-morpholin-4-ylethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   3-[(2-benzyl-3-oxo-1,2,3,4,5,7-hexahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methyl]benzonitrile;-   6-(3-chlorobenzyl)-2-(2-piperidin-1-ylethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   3-{[2-(1,3-benzodioxol-5-yl)-3-oxo-1,2,3,4,5,7-hexahydro-6H-pyrazolo[3,4-c]pyridin-6-yl]methyl}benzonitrile;-   3-[6-(3-chlorobenzyl)-3-oxo-1,3,4,5,6,7-hexahydro-2H-pyrazolo[3,4-c]pyridin-2-yl]benzonitrile;-   3-{[2-(3-methoxyphenyl)-3-oxo-1,2,3,4,5,7-hexahydro-6H-pyrazolo[3,4-c]pyridin-6-yl]methyl}benzonitrile;-   3-{[2-(2-methoxyethyl)-3-oxo-1,2,3,4,5,7-hexahydro-6H-pyrazolo[3,4-c]pyridin-6-yl]methyl}benzonitrile;-   6-(3-chlorobenzyl)-2-[2-(4-chlorophenoxy)ethyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   2-benzyl-6-[(4-methylphenyl)sulfonyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   6-(2-methoxybenzyl)-2-(3-methoxyphenyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   6-(4-chlorobenzyl)-2-(1-methylpiperidin-4-yl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   3-{[2-(2-hydroxyethyl)-3-oxo-1,2,3,4,5,7-hexahydro-6H-pyrazolo[3,4-c]pyridin-6-yl]methyl}benzonitrile;-   2-benzyl-6-(pyridin-3-ylmethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   2-benzyl-6-(pyridin-2-ylmethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   2-(1-benzylpiperidin-4-yl)-6-(3-chlorobenzyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   2-benzyl-6-[(2-methyl-1,3-thiazol-4-yl)methyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   2-benzyl-6-(methylsulfonyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   6-(3-chlorobenzyl)-2-(3-hydroxybenzyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   6-(3-chlorobenzyl)-2-(pyridin-3-ylmethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   6-(3-chlorobenzyl)-2-(1-phenylethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   3-{[2-(4-chlorophenyl)-3-oxo-1,2,3,4,5,7-hexahydro-6H-pyrazolo[3,4-c]pyridin-6-yl]methyl}benzonitrile;-   3-{[2-(1-methylpiperidin-4-yl)-3-oxo-1,2,3,4,5,7-hexahydro-6H-pyrazolo[3,4-c]pyridin-6-yl]methyl}benzonitrile;-   6-(3-chlorobenzyl)-2-(4-methoxyphenyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   2-benzyl-6-(2-methoxybenzyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one-   6-(4-chlorobenzyl)-2-(2-chloro-4-fluorobenzyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   6-(3-chlorobenzyl)-2-(2-chloro-4-fluorobenzyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   3-[6-(3-cyanobenzyl)-3-oxo-1,3,4,5,6,7-hexahydro-2H-pyrazolo[3,4-c]pyridin-2-yl]benzonitrile;-   6-(4-chlorobenzyl)-2-(2-piperidin-1-ylethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   3-{[2-(3-methoxybenzyl)-3-oxo-1,2,3,4,5,7-hexahydro-6H-pyrazolo[3,4-c]pyridin-6-yl]methyl}benzonitrile;-   N-{3-[6-(3-cyanobenzyl)-3-oxo-1,3,4,5,6,7-hexahydro-2H-pyrazolo[3,4-c]pyridin-2-yl]phenyl}acetamide;-   3-{[2-(2-chloro-4-fluorobenzyl)-3-oxo-1,2,3,4,5,7-hexahydro-6H-pyrazolo[3,4-c]pyridin-6-yl]methyl}benzonitrile;-   2-(4-chlorophenyl)-6-(pyridin-3-ylmethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   3-{[2-(2-morpholin-4-ylethyl)-3-oxo-1,2,3,4,5,7-hexahydro-6H-pyrazolo[3,4-c]pyridin-6-yl]methyl}benzonitrile;-   N-{3-[6-(3-chlorobenzyl)-3-oxo-1,3,4,5,6,7-hexahydro-2H-pyrazolo[3,4-c]pyridin-2-yl]phenyl}acetamide;-   2-(1,3-benzodioxol-5-yl)-6-(pyridin-3-ylmethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   2-(4-chlorophenyl)-6-[(6-chloropyridin-3-yl)methyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   2-(4-chlorophenyl)-6-[4-(methylsulfonyl)benzyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one-   2-(1,3-benzodioxol-5-yl)-6-[3-(trifluoromethyl)benzyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   2-(1,3-benzodioxol-5-yl)-6-[(6-chloropyridin-3-yl)methyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   6-(3-chloro-4-fluorobenzyl)-2-(1-methylpiperidin-4-yl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   6-(3-chloro-4-fluorobenzyl)-2-(2-morpholin-4-ylethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   2-benzyl-6-(3-chloro-4-fluorobenzyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   2-(2-morpholin-4-ylethyl)-6-[3-(trifluoromethyl)benzyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   6-(3-chlorobenzyl)-2-(4-methoxybenzyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   3-[(2-benzyl-3-oxo-1,2,3,4,5,7-hexahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)sulfonyl]benzonitrile;-   2-(4-chlorophenyl)-6-[(4-methylphenyl)sulfonyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   6-(1H-benzimidazol-2-ylmethyl)-2-benzyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   2-benzyl-6-(pyridin-3-ylsulfonyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   2-(2-methyl-1,3-benzothiazol-6-yl)-6-(pyridin-2-ylmethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   3-{[2-(4-cyanophenyl)-3-oxo-1,2,3,4,5,7-hexahydro-6H-pyrazolo[3,4-c]pyridin-6-yl]methyl}benzonitrile;-   2-benzyl-6-[4-(methylsulfonyl)benzyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   2-(2-methyl-1,3-benzothiazol-6-yl)-6-(pyridin-3-ylmethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   6-(4-chlorobenzyl)-2-(2-morpholin-4-ylethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   3-{6-[(6-chloropyridin-3-yl)methyl]-3-oxo-1,3,4,5,6,7-hexahydro-2H-pyrazolo[3,4-c]pyridin-2-yl}benzonitrile;-   2-benzyl-6-[(6-chloropyridin-3-yl)methyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   3-[3-oxo-6-(pyridin-3-ylmethyl)-1,3,4,5,6,7-hexahydro-2H-pyrazolo[3,4-c]pyridin-2-yl]benzonitrile;-   6-(4-chlorobenzyl)-2-(2-methyl-1,3-benzothiazol-6-yl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   N-{3-[3-oxo-6-(pyridin-3-ylmethyl)-1,3,4,5,6,7-hexahydro-2H-pyrazolo[3,4-c]pyridin-2-yl]phenyl}acetamide;-   6-(3-chloro-4-fluorobenzyl)-2-(2-methoxyethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   2-(2-methoxyethyl)-6-(pyridin-3-ylmethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   6-(3,5-dichlorobenzyl)-2-(2-morpholin-4-ylethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   2-(1-phenylethyl)-6-(pyridin-3-ylmethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   2-(4-chlorophenyl)-6-(pyridin-2-ylmethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   2-(2-chloro-4-fluorobenzyl)-6-(pyridin-3-ylmethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   6-(3-chlorobenzyl)-2-[1,2,4]triazolo[4,3-b]pyridazin-6-yl-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   6-(3-chlorobenzyl)-2-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   3-[(2-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-3-oxo-1,2,3,4,5,7-hexahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methyl]benzonitrile;-   6-(3-chloro-4-fluorobenzyl)-2-(4-chlorophenyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   2-(2-chloro-4-fluorobenzyl)-6-[(6-chloropyridin-3-yl)methyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   4-{6-[(6-chloropyridin-3-yl)methyl]-3-oxo-1,3,4,5,6,7-hexahydro-2H-pyrazolo[3,4-c]pyridin-2-yl}benzonitrile;-   2-(2-chloro-4-fluorobenzyl)-6-[3-(trifluoromethyl)benzyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   6-(3-chloro-4-fluorobenzyl)-2-(2-methyl-1,3-benzothiazol-6-yl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   2-(2-methyl-1,3-benzothiazol-6-yl)-6-[3-(trifluoromethyl)benzyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   2-(2-benzyl-3-oxo-1,2,3,4,5,7-hexahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-N-methylacetamide;-   3-{[2-(2,3-dihydro-1,4-benzo    dioxin-6-yl)-3-oxo-1,2,3,4,5,7-hexahydro-6H-pyrazolo[3,4-c]pyridin-6-yl]methyl}benzonitrile;-   2-benzyl-6-[(1-methyl-1H-pyrazol-3-yl)methyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   3-{6-[4-(methylsulfonyl)benzyl]-3-oxo-1,3,4,5,6,7-hexahydro-2H-pyrazolo[3,4-c]pyridin-2-yl}benzonitrile;-   3-[6-(3-chloro-4-fluorobenzyl)-3-oxo-1,3,4,5,6,7-hexahydro-2H-pyrazolo[3,4-c]pyridin-2-yl]benzonitrile;-   6-[(6-chloropyridin-3-yl)methyl]-2-(2-methyl-1,3-benzothiazol-6-yl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   3-{3-oxo-6-[3-(trifluoromethyl)benzyl]-1,3,4,5,6,7-hexahydro-2H-pyrazolo[3,4-c]pyridin-2-yl}benzonitrile;-   6-[(6-chloropyridin-3-yl)methyl]-2-(2-fluorophenyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   4-[3-oxo-6-(pyridin-3-ylmethyl)-1,3,4,5,6,7-hexahydro-2H-pyrazolo[3,4-c]pyridin-2-yl]benzonitrile;-   N-(3-{6-[(6-chloropyridin-3-yl)methyl]-3-oxo-1,3,4,5,6,7-hexahydro-2H-pyrazolo[3,4-c]pyridin-2-yl}phenyl)acetamide;-   6-(3-chlorobenzyl)-2-[4-(trifluoromethyl)phenyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   6-(3-chlorobenzyl)-2-(4-chloro-2-fluorophenyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   6-(pyridin-3-ylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   2-(4-methoxyphenyl)-6-(pyridin-3-ylmethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   2-[3-(benzyloxy)phenyl]-6-[(4-methylphenyl)sulfonyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   N-{4-[(2-benzyl-3-oxo-1,2,3,4,5,7-hexahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methyl]phenyl}acetamide;-   6-(3-chlorobenzyl)-2-(3-fluorobenzyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   6-(3-chlorobenzyl)-2-(4-fluorobenzyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   6-(3-chlorobenzyl)-2-[2-(dimethylamino)benzyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   5-[(2-benzyl-3-oxo-1,2,3,4,5,7-hexahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methyl]-2-fluorobenzonitrile;-   2-benzyl-6-(quinolin-2-ylmethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;    3-{[2-(2-methyl-1,3-benzothiazol-6-yl)-3-oxo-1,2,3,4,5,7-hexahydro-6H-pyrazolo[3,4-c]pyridin-6-yl]methyl}benzonitrile;-   2-benzyl-6-[(6-chloropyridin-2-yl)methyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   2-benzyl-6-(3-methoxybenzyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   2-benzyl-6-(4-methoxybenzyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   2-benzyl-6-[(5-methylisoxazol-3-yl)methyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   6-(1,3-benzothiazol-2-ylmethyl)-2-benzyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   3-[6-(4-chlorobenzyl)-3-oxo-1,3,4,5,6,7-hexahydro-2H-pyrazolo[3,4-c]pyridin-2-yl]propanenitrile;-   2-benzyl-6-[(3-fluorophenyl)sulfonyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   2-benzyl-6-[(3-methoxyphenyl)sulfonyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   2-benzyl-6-[(3-chlorophenyl)sulfonyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   2-benzyl-6-[(4-methoxyphenyl)sulfonyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   2-benzyl-6-[(4-chlorophenyl)sulfonyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   2-benzyl-6-[(4-fluorophenyl)sulfonyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   2-benzyl-6-[(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl)sulfonyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   2-benzyl-6-(quinolin-8-ylsulfonyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   3-{[3-oxo-2-(2-phenylethyl)-1,2,3,4,5,7-hexahydro-6H-pyrazolo[3,4-c]pyridin-6-yl]methyl}benzonitrile;-   3-{[2-(4-methoxyphenyl)-3-oxo-2,3,3a,4,5,7-hexahydro-6H-pyrazolo[3,4-c]pyridin-6-yl]methyl}benzonitrile;-   6-[(4-methylphenyl)sulfonyl]-2-(2-phenoxyethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   6-(3-chlorobenzyl)-2-(pyridin-4-ylmethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   6-[(4-methylphenyl)sulfonyl]-2-phenyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   2-(diphenylmethyl)-6-(pyridin-3-ylmethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   6-[(4-methylphenyl)sulfonyl]-2-(2-morpholin-4-ylethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   6-[(4-methylphenyl)sulfonyl]-2-(pyridin-2-ylmethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   6-[(4-methylphenyl)sulfonyl]-2-(1-methylpiperidin-4-yl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   2-(imidazo[1,2-a]pyridin-2-ylmethyl)-6-[(4-methylphenyl)sulfonyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   3-{6-[(4-methylphenyl)sulfonyl]-3-oxo-1,3,4,5,6,7-hexahydro-2H-pyrazolo[3,4-c]pyridin-2-yl}propanenitrile;-   2-[2-(dimethylamino)benzyl]-6-[(4-methylphenyl)sulfonyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   6-[(4-methylphenyl)sulfonyl]-2-(pyridin-4-ylmethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   2-[2-(dimethylamino)ethyl]-6-[(4-methylphenyl)sulfonyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   2-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-6-(methylsulfonyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   6-[(3-chloro-4-fluorophenyl)sulfonyl]-2-(imidazo[1,2-a]pyridin-2-ylmethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   6-[(4-methylphenyl)sulfonyl]-2-quinoxalin-2-yl-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   6-[(4-methylphenyl)sulfonyl]-2-(pyridin-3-ylmethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   6-[(4-methylphenyl)sulfonyl]-2-pyridin-2-yl-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   6-[(3,4-dichlorophenyl)sulfonyl]-2-(imidazo[1,2-a]pyridin-2-ylmethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   2-(7-chloroquinolin-4-yl)-6-[(4-methylphenyl)sulfonyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   N-(3-{6-[(4-methylphenyl)sulfonyl]-3-oxo-1,3,4,5,6,7-hexahydro-2H-pyrazolo[3,4-c]pyridin-2-yl}phenyl)acetamide;-   6-(biphenyl-4-ylsulfonyl)-2-(imidazo[1,2-a]pyridin-2-ylmethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   2-(imidazo[1,2-a]pyridin-2-ylmethyl)-6-{[3-(trifluoromethyl)phenyl]sulfonyl}-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   2-benzyl-6-(phenylsulfonyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   2-(2-morpholin-4-ylethyl)-6-(phenylsulfonyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   6-[(4-chlorophenyl)sulfonyl]-2-phenyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   2-benzyl-6-[(4-tert-butylphenyl)sulfonyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   2-(1-benzylpiperidin-4-yl)-6-[(4-methylphenyl)sulfonyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;-   6-[(4-chlorophenyl)sulfonyl]-2-(2-morpholin-4-ylethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one;    and-   2-[2-fluoro-4-(methylsulfonyl)phenyl]-6-[(4-methylphenyl)sulfonyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one.

In another embodiment, the invention provides a method for treating apatient suffering from a disease or condition selected fromcardiovascular disorders, respiratory disorders, metabolism disorders,skin disorders, bone disorders, neuroinflammatory and/orneurodegenerative disorders, kidney diseases, reproduction disorders,diseases affecting the eye and/or the lens and/or conditions affectingthe inner ear, inflammatory disorders, liver diseases, pain, cancersallergic disorders, traumatisms, septic, hemorrhagic and anaphylacticshock, disorders of the gastrointestinal system, angiogenesis,angiogenesis-dependent conditions and other diseases and disordersassociated with Nicotinamide adenine dinucleotide phosphate oxidase(NADPH Oxidase). The method comprises administering a compound accordingto Formula (I) in a patient in need thereof.

In another embodiment, the invention provides a method for inhibitingangiogenesis in a patient in need thereof, wherein the method comprisesadministering an angiogenesis inhibiting dose of a compound of Formula(I) in a patient in need thereof.

In another embodiment, the invention provides a method of inhibitingtumor neovascularization by inhibiting tumor angiogenesis according tothe present methods. Similarly, the invention provides a method forinhibiting tumor growth by practicing the angiogenesis-inhibitingmethods.

In a particular embodiment, the compounds and methods of the inventionare contemplated for use in treatment of a tumor tissue of a patientwith a tumor, solid tumor, a metastasis, a cancer, a melanoma, a skincancer, a breast cancer, a hemangioma or angiofibroma and the likecancer, and the angiogenesis to be inhibited is tumor tissueangiogenesis where there is neovascularization of a tumor tissue.Typical solid tumor tissues treatable by the present compounds andmethods include, but are not limited to, tumors of the skin, melanoma,lung, pancreas, breast, colon, laryngeal, ovarian, prostate, colorectal,head, neck, testicular, lymphoid, marrow, bone, sarcoma, renal, sweatgland, and the like tissues. Further examples of cancers treated areglioblastomas.

In another particular embodiment, the compounds and methods of theinvention are contemplated for use in treatment of an inflamed tissueand the angiogenesis to be inhibited is inflamed tissue angiogenesiswhere there is neovascularization of inflamed tissue. In this case, thecompound and method according to the invention contemplate theinhibition of angiogenesis in arthritic tissues, such as in a patientwith chronic articular rheumatism, in immune or non-immune inflamedtissues, in psoriatic tissue and the like.

In embodiments, the invention contemplates inhibition of angiogenesis ina tissue. The extent of angiogenesis in a tissue, and therefore theextent of inhibition achieved by the present methods, can be evaluatedby a variety of methods, such as are described herein.

According to an embodiment of the invention, the disease or condition isa cancer.

According to an embodiment of the invention, the compound according tothe invention is to be administered in combination with a co-agentuseful in the treatment of cancer.

According to an embodiment of the invention, the compound according tothe invention is to be administered in combination with radiationtherapy.

In another embodiment, the invention provides a pharmaceuticalcomposition containing at least one derivative pyrazolo piperidineaccording to Formula (I) and a pharmaceutically acceptable carrier,diluent or excipient thereof.

The compounds of invention have been named according the IUPAC standardsused in the program ACD/Name (product version 10.01).

Compounds according to the present invention comprise a compoundaccording to Formula (I), its tautomers, its geometrical isomers, itsoptically active forms as enantiomers, diastereomers and its racemateforms, as well as pharmaceutically acceptable salts thereof.

References cited herein are hereby incorporated by reference in theirentirety. The present invention is not to be limited in scope by thespecific embodiments described herein, which are intended as singleillustrations of individual aspects of the invention, and functionallyequivalent methods and components are within the scope of the invention.Indeed, various modifications of the invention, in addition to thoseshown and described herein will become apparent to those skilled in theart from the foregoing description. Such modifications are intended tofall within the scope of the appended claims.

The invention having been described, the following examples arepresented by way of illustration, and not limitation.

Synthesis of Compounds of the Invention:

The novel derivatives according to Formula (I) can be prepared fromreadily available starting materials using the following general methodsand procedures. It will be appreciated that where typical or preferredexperimental conditions (i.e. reaction temperatures, time, moles ofreagents, solvents etc.) are given, other experimental conditions canalso be used unless otherwise stated. Optimum reaction conditions mayvary with the particular reactants or solvents used, but such conditionscan be determined by the person skilled in the art, using routineoptimisation procedures.

The general synthetic approach for obtaining compounds of Formula (I) isdepicted in Scheme 1 below.

Pyrazolo piperidine derivatives according to Formula (I), whereby thesubstituents R¹ and R³, are as above defined, may be prepared in threechemical steps, from custom made or commercially available substitutedpiperidine derivatives according to Formula (VI), alkyl halidesaccording to Formula (IV) and hydrazine derivatives according to Formula(II), following the synthetic protocol outlined in Scheme 1 above. In amore specific method, a piperidine derivative according to Formula (VI)wherein R¹⁸ is defined as above is subjected to hydrogenolysis usinghydrogen and a catalyst such as palladium on carbon, in neutral andunder refluxing conditions in a suitable solvent like ethanol, methanolor other unreactive solvents over time depending of the intrinsicreactivity of compounds according to Formula (VI) to give thecorresponding benzyl deprotected piperidine derivatives according toFormula (V). In a subsequent step, the piperidine derivatives of Formula(V) were treated with an alkylating agent of Formula (IV) such as alkylchlorides, bromides, iodides or mesylates, wherein R³ is defined asabove, in presence of a suitable base, e.g. Triethylamine, di-isopropylethyl amine, sodium hydride or potassium carbonate as a base in asuitable solvent, e.g. dichloromethane, N,N-dimethyl formamide ortetrahydrofuran, by traditional thermic method or using microwavetechnology. The intermediate compounds according to Formula (III) arefurther reacted with a hydrazine derivative according to Formula (II),wherein R¹ is defined as above. The pyrazolo derivatives according toFormula (Ib), i.e. of Formula (I) wherein R² is H, are isolated aftercyclisation, preferably in protic solvents in presence of a base such assodium methanolate, sodium isopropanolate or the like, using standardrefluxing conditions well known to the person skilled in the art.

The following abbreviations refer respectively to the definitions below:

Å (Angström), min (minute), h (hour), g (gram), MHz (Megahertz), mL(milliliter), mm (millimeter), mmol (millimole), M (molar), ng(nanogram), nm (nanometer), rt (room temperature), BLM (Bleomycin), BSA(Bovine serum albumin), DCF (2,7-dichlorodihydrofluorescein), DCM(dichloromethane), DMSO (Dimethyl Sulfoxide), DAPI (4,6Diamidino-2-phenylindole), DPI (Diphenyl-iodonium), EDTA(ethylenediaminetetraacetic acid), EGF (Epidermal Growth Factor), EtOAc(Ethyl acetate), FCS (Foetal Calf Serum), HBSS (Hank's Buffered SaltSolution), HPLC (High performance liquid chromatography), H₂DCF-DA(2′,7′-dichlorodihydrofluorescein diacetate), MEM(2-methoxyethoxymethyl), MS (Mass Spectrometry), NADPH (Nicotinamideadenine dinucleotide diphosphate reduced form), NBT (Nitrobluetetrazolium), NMR (Nuclear magnetic resonance), OD (Optical Density),PBS (Phosphate Buffered Saline), TFA (Trifluoroacetic acid), TGF-β(Tumor Growth Factor beta), ROS (Reactive oxygen species), SOD(Superoxide dismutase), TLC (Thin layer chromatography), UPLC (ultraperformance liquid chromatography), UV (Ultraviolet).

If the above set of general synthetic methods is not applicable toobtain compounds according to Formula (I) and/or necessary intermediatesfor the synthesis of compounds of Formula (I), suitable methods ofpreparation known by a person skilled in the art should be used. Ingeneral, the synthesis pathways for any individual compound of Formula(I) will depend on the specific substituents of each molecule and uponthe ready availability of intermediates necessary; again such factorsbeing appreciated by those of ordinary skill in the art. For all theprotection and deprotection methods, see Philip J. Kocienski, in“Protecting Groups”, Georg Thieme Verlag Stuttgart, 2005 and Theodora W.Greene and Peter G. M Wuts in “Protective Groups in Organic Synthesis”,Wiley Interscience, 4^(th) Edition 2006.

Compounds of this invention can be isolated in association with solventmolecules by crystallization from evaporation of an appropriate solvent.The pharmaceutically acceptable acid addition salts of the compounds ofFormula (I), which contain a basic center, may be prepared in aconventional manner. For example, a solution of the free base may betreated with a suitable acid, either neat or in a suitable solution, andthe resulting salt isolated either by filtration or by evaporation undervacuum of the reaction solvent. Pharmaceutically acceptable baseaddition salts may be obtained in an analogous manner by treating asolution of compound of Formula (I) with a suitable base. Both types ofsalts may be formed or interconverted using ion-exchange resintechniques.

In the following the present invention shall be illustrated by means ofsome examples, which are not to be viewed as limiting the scope of theinvention.

The HPLC, NMR and MS data provided in the examples described below areobtained as followed: HPLC: column Waters Symmetry C8 50×4.6 mm,Conditions: MeCN/H₂O, 5 to 100% (8 min), max plot 230-400 nm; Massspectra: PE-SCIEX API 150 EX (APCI and ESI), LC/MS spectra: Waters ZMD(ES); ¹H-NMR: Bruker DPX-300 MHz.

The preparative HPLC purifications are performed with HPLC Waters PrepLC 4000 System equipped with columns Prep Nova-Pak®HR C186 μm 60 Å,40×30 mm (up to 100 mg) or with XTerra® Prep MS C8, 10 μm, 50×300 mm (upto 1 g). All the purifications are performed with a gradient of MeCN/H₂O0.09% TFA; UV detection at 254 nm and 220 nm; flow 20 mL/min (up to 50mg). TLC Analysis is performed on Merck Precoated 60 F₂₅₄ plates.Purifications by flash chromatography are performed on SiO₂ support,using cyclohexane/EtOAc or DCM/MeOH mixtures as eluents.

Example 1 Formation of2-(4-chlorophenyl)-6-(pyridin-2-ylmethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one(94) (Compound Ib, Scheme 1)

a) ethyl 3-oxopiperidine-4-carboxylate (Compound of Formula (V), Scheme1)

To a suspension of 1.0 g of Pd—C (10 wt. %) was added ethyl1-benzyl-3-oxopiperidine-4-carboxylate hydrochloride (10.0 g, 33.58mmol) (Sigma-Aldrich) dissolved in Ethanol (120 mL). The reactionmixture was then heated at 50° C. under a hydrogen atmosphere (balloon)at atmospheric pressure and followed by HPLC and UPLC-MS. After 4 h at50° C., the analyses revealed full conversion of the reaction. Aftercooling to room temperature, the crude mixture was filtered throughcelite. The celite was washed with EtOH and the filtrate wasconcentrated in vacuo to give the desired ethyl3-oxopiperidine-4-carboxylate hydrochloride as an off-white solid (5.84g, 28.12 mmol, 84% yield). ¹HNMR (500 MHz, DMSO-d6): 1.25 (t, J 7.3 Hz,3H); 2.58 (t, J 6.3 Hz, 2H); 3.26 (t, J 6.3 Hz, 2H); 3.67 (s, 2H), 7.22(q, J 7.3 Hz, 2H); 9.50 (s, br, 1H); 11.90 (s, br, 1H).

b) ethyl 3-oxo-1-(pyridin-2-ylmethyl)piperidine-4-carboxylate (III),Scheme 1)

The mixture of the above obtained ethyl 3-oxopiperidine-4-carboxylatehydrochloride (Compound of Formula (V), 0.525 g, 2.530 mmol), 0.150 g(7.590 mmol 1.32 ml of diisopropylethylamine 0.379 g (2.530 mmol) ofsodium iodide and 0.414 g (2.530 mmol) of 2-(chloromethyl)pyridinehydrochloride were stirred at 80° C. in 5.0 ml of anhydrous CH₃CN. Thereaction was monitored by HPLC and UPLC-MS. After 1 h at 80° C., theinsoluble inorganic materials were filtered off and the filtrate wasconcentrated in vacuo to give an orange residue. This residue wasdissolved in CH₂Cl₂, washed with brine, H₂O, dried over Na₂SO₄ andconcentrated in vacuo to give pure ethyl3-oxo-1-(pyridin-2-ylmethyl)piperidine-4-carboxylate (0.663 g, 2.530mmol, quantitative yield). The product was used for the next stepwithout further manipulation. 263.2.

c)6-benzyl-2-(2-chloro-4-fluorophenyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one(Compound of Formula (Ib), Scheme 1)

In a three-necked flask, under a azote atmosphere, 0.217 g (1.212 mmol)of (4-chlorophenyl)hydrazine hydrochloride and 0.318 g (1.212 mmol) ofethyl 3-oxo-1-(pyridin-2-ylmethyl)piperidine-4-carboxylate hydrochlorideobtained above were stirred in 3.0 mL of EtOH for 1 h at 60° C. HPLC andUHPLC-MS analyses revealed the formation of the corresponding hydrazoneintermediate. After cooling to rt, a solution of EtONa/EtOH—prepared bydissolution of 70 mg (3.031 mmol) of Na in 3.5 mL of EtOH—was added tothe reaction mixture and it was stirred for 1 additional hour at roomtemperature (reaction monitored by HPLC and UPLC-MS). The crude mixturewas then concentrated in vacuo to give a beige residue that was thenpartitioned between 10.0 mL of CH₂Cl₂ and 3.0 mL of H₂O. The aqueousphase was separated and revealed to contain the desired product whereasonly by-products of the reaction were present in the organic phase. Theaqueous phase was therefore purified by reverse-phase chromatography(H₂O as eluent, isochratic). Lyophilisation of the pure fractions in thedesired product afforded 130 mg of the desired6-benzyl-2-(2-chloro-4-fluorophenyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-oneas a white solid (31% yield).

1HNMR (500 MHz, CD3OD): 2.52 (t, J 5.7 Hz, 2H); 2.77 (t, J 5.7 Hz, 2H);3.50 (s, 2H), 3.86 (s, 2H); 7.28-7.31 (m, 2H), 7.32-7.35 (m, 1H); 7.63(d, J 7.6 Hz, 1H); 7.80-7.83 (m, 2H); 7.83-7.86 (m, 1H); 8.48-8.50 (m,1H). 341.2.

The structures of further compounds synthesised herein are listed in thefollowing Table 1:

TABLE 1 Data MS Compound Structure Name (ESI⁺) Method 1

6-benzyl-2-(2-chloro-4- fluorophenyl)- 1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c] pyridin-3-one 358.9 Ex. 94, Scheme 1 2

6-benzyl-2-[3-(benzyl oxy)phenyl]-1,2,4,5,6,7- hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one 412.7 Ex. 94, Scheme 1 3

6-benzyl-2-(4-chloro benzyl)-1,2,4,5,6,7- hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one 355.2 Ex. 94, Scheme 1 4

6-benzyl-1,2,4,5,6,7- hexahydro-3H-pyrazolo [3,4-c]pyridin-3-one 230.4Ex. 94, Scheme 1 5

2,6-dibenzyl-1,2,4,5,6,7- hexahydro-3H-pyrazolo [3,4-c]pyridin-3-one320.7 Ex. 94, Scheme 1 6

6-benzyl-2-(3-methoxy phenyl)-1,2,4,5,6,7- hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one 336.6 Ex. 94, Scheme 1 7

6-benzyl-2-(3-chloro phenyl)-1,2,4,5,6,7- hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one 340.9 Ex. 94, Scheme 1 8

6-benzyl-2-phenyl- 1,2,4,5,6,7-hexahydro- 3H-pyrazolo[3,4-c]pyridin-3-one 306.5 Ex. 94, Scheme 1 9

6-benzyl-2-methyl- 1,2,4,5,6,7-hexahydro- 3H-pyrazolo[3,4-c]pyridin-3-one 244.3 Ex. 94, Scheme 1 10

6-(3-chlorobenzyl)-2-(3- methoxyphenyl)- 1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c] pyridin-3-one 371.0 Ex. 94, Scheme 1 11

6-(3,5-dimethoxy benzyl)-2-(3-methoxy phenyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo [3,4-c]pyridin-3-one 396.7 Ex. 94, Scheme 1 12

6-benzyl-2-(2-methoxy phenyl)-1,2,4,5,6,7- hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one 336.4 Ex. 94, Scheme 1 13

6-(4-chlorobenzyl)-2-(3- methoxyphenyl)- 1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c] pyridine-3-one 371.1 Ex. 94, Scheme 1 14

6-(2,4-dichlorobenzyl)- 2-(3-methoxyphenyl)- 1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4- c]pyridin-3-one 405.8 Ex. 94, Scheme 1 15

2-benzyl-6-(3-chloro benzyl)-1,2,4,5,6,7- hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one 355.0 Ex. 94, Scheme 1 16

6-(3-chlorobenzyl)-2-(2- hydroxyethyl)- 1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c] pyridin-3-one 308.9 Ex. 94, Scheme 1 17

6-(3-chlorobenzyl)-2-(3- methoxybenzyl)- 1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c] pyridin-3-one 385.0 Ex. 94, Scheme 1 18

6-(3-chlorobenzyl)-2-(2- methoxybenzyl)- 1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4- c]pyridin-3-one 384.9 Ex. 94, Scheme 1 19

6-(3-chlorobenzyl)- 1,2,4,5,6,7-hexahydro- 3H-pyrazolo[3,4-c]pyridin-3-one 264.8 Ex. 94, Scheme 1 20

6-(3-chlorobenzyl)-2-(1- methylpiperidin-4-yl)- 1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c] pyridin-3-one 362.0 Ex. 94, Scheme 1 21

2-benzyl-6-(4- chlorobenzyl)- 1,2,4,5,6,7-hexahydro- 3H-pyrazolo[3,4-c]pyridin-3-one 354.9 Ex. 94, Scheme 1 22

6-(4-chlorobenzyl)-2-(2- methoxybenzyl)- 1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c] pyridin-3-one 384.9 Ex. 94, Scheme 1 23

6-(4-chlorobenzyl)-2-(3- methoxybenzyl)- 1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c] pyridin-3-one 385.1 Ex. 94, Scheme 1 24

6-(4-chlorobenzyl)-2-(2- hydroxyethyl)- 1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c] pyridin-3-one 308.9 Ex. 94, Scheme 1 25

2-(3-methoxyphenyl)-6- (1-phenylethyl)- 1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c] pyridin-3-one 350.6 Ex. 94, Scheme 1 26

6-(3-chlorobenzyl)-2-(2- methoxyethyl)- 1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c] pyridin-3-one 322.8 Ex. 94, Scheme 1 27

6-(4-chlorobenzyl)-2-(2- methoxyethyl)- 1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c] pyridin-3-one 322.9 Ex. 94, Scheme 1 28

2-(1,3-benzodioxol-5- yl)-6-(4-chlorobenzyl)- 1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c] pyridin-3-one 384.8 Ex. 94, Scheme 1 29

2-(1,3-benzodioxol-5- yl)-6-(3-chlorobenzyl)- 1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c] pyridin-3-one 384.9 Ex. 94, Scheme 1 30

4-[6-(3-chlorobenzyl)-3- oxo-1,3,4,5,6,7- hexahydro-2H-pyrazolo[3,4-c]pyridin-2-yl] benzonitrile 365.8 Ex. 94, Scheme 1 31

6-(3-chlorobenzyl)-2-(4- chlorophenyl)- 1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c] pyridin-3-one 375.5 Ex. 94, Scheme 1 32

6-(3-chlorobenzyl)-2-(2- morpholin-4-ylethyl)- 1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c] pyridin-3-one 377.9 Ex. 94, Scheme 1 33

3-[(2-benzyl-3-oxo- 1,2,3,4,5,7-hexahydro- 6H-pyrazolo[3,4-c]pyridin-6-yl)methyl] benzonitrile 345.6 Ex. 94, Scheme 1 34

6-(3-chlorobenzyl)-2-(2- piperidin-1-ylethyl)- 1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c] pyridin-3-one 376.0 Ex. 94, Scheme 1 35

3-{[2-(1,3-benzodioxol- 5-yl)-3-oxo-1,2,3,4,5,7- hexahydro-6H-pyrazolo[3,4-c]pyridin-6-yl] methyl}benzonitrile 375.6 Ex. 94, Scheme 1 36

3-[6-(3-chlorobenzyl)-3- oxo-1,3,4,5,6,7- hexahydro-2H-pyrazolo[3,4-c]pyridin-2-yl] benzonitrile 365.9 Ex. 94, Scheme 1 37

3-{[2-(3-methoxy phenyl)-3-oxo- 1,2,3,4,5,7-hexahydro-6H-pyrazolo[3,4-c] pyridin-6-yl]methyl} benzonitrile 361.6 Ex. 94,Scheme 1 38

3-{[2-(2-methoxyethyl)- 3-oxo-1,2,3,4,5,7- hexahydro-6H-pyrazolo[3,4-c]pyridin-6-yl] methyl}benzonitrile 313.6 Ex. 94, Scheme 1 39

6-(3-chlorobenzyl)-2-[2- (4-chlorophenoxy)ethyl]- 1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c] pyridin-3-one 419.7 Ex. 94, Scheme 1 40

2-benzyl-6-[(4-methyl phenyl)sulfonyl]- 1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c] pyridin-3-one 384.5 Ex. 94, Scheme 1 41

6-(2-methoxybenzyl)-2- (3-methoxyphenyl)- 1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c] pyridin-3-one 366.4 Ex. 94, Scheme 1 42

6-(4-chlorobenzyl)-2-(1- methylpiperidin-4-yl)- 1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c] pyridin-3-one 362.0 Ex. 94, Scheme 1 43

3-{[2-(2-hydroxyethyl)- 3-oxo-1,2,3,4,5,7- hexahydro-6H-pyrazolo[3,4-c]pyridin-6-yl] methyl}benzonitrile 299.4 Ex. 94, Scheme 1 44

2-benzyl-6-(pyridin-3-yl methyl)-1,2,4,5,6,7- hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one 321.5 Ex. 94, Scheme 1 45

2-benzyl-6-(pyridin-2-yl methyl)-1,2,4,5,6,7- hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one 321.5 Ex. 94, Scheme 1 46

2-(1-benzylpiperidin-4- yl)-6-(3-chlorobenzyl)- 1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c] pyridin-3-one 438.1 Ex. 94, Scheme 1 47

2-benzyl-6-[(2-methyl- 1,3-thiazol-4-yl)methyl]- 1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c] pyridin-3-one 341.9 Ex. 94, Scheme 1 48

2-benzyl-6-(methyl sulfonyl)-1,2,4,5,6,7- hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one 308.5 Ex. 94, Scheme 1 49

6-(3-chlorobenzyl)-2-(3- hydroxybenzyl)- 1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c] pyridin-3-one 370.9 Ex. 94, Scheme 1 50

6-(3-chlorobenzyl)-2- (pyridin-3-ylmethyl)- 1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c] pyridin-3-one 355.9 Ex. 94, Scheme 1 51

6-(3-chlorobenzyl)-2-(1- phenylethyl)-1,2,4,5,6,7- hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one 369.0 Ex. 94, Scheme 1 52

3-{[2-(4-chlorophenyl)- 3-oxo-1,2,3,4,5,7- hexahydro-6H-pyrazolo[3,4-c]pyridin-6- yl]methyl}benzonitrile 365.8 Ex. 94, Scheme 1 53

3-{[2-(1-methyl piperidin-4-yl)-3-oxo- 1,2,3,4,5,7-hexahydro-6H-pyrazolo[3,4-c] pyridin-6-yl]methyl} benzonitrile 352.6 Ex. 94,Scheme 1 54

6-(3-chlorobenzyl)-2-(4- methoxyphenyl)- 1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c] pyridin-3-one 371.0 Ex. 94, Scheme 1 55

2-benzyl-6-(2-methoxy benzyl)-1,2,4,5,6,7- hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one 350.6 Ex. 94, Scheme 1 56

6-(4-chlorobenzyl)-2-(2- chloro-4-fluorobenzyl)- 1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c] pyridin-3-one 407.5 Ex. 94, Scheme 1 57

6-(3-chlorobenzyl)-2-(2- chloro-4-fluorobenzyl)- 1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c] pyridin-3-one 407.5 Ex. 94, Scheme 1 58

3-[6-(3-cyanobenzyl)-3- oxo-1,3,4,5,6,7- hexahydro-2H-pyrazolo[3,4-c]pyridin-2-yl] benzonitrile 356.6 Ex. 94, Scheme 1 59

6-(4-chlorobenzyl)-2-(2- piperidin-1-ylethyl)- 1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c] pyridin-3-one 375.9 Ex. 94, Scheme 1 60

3-{[2-(3-methoxy benzyl)-3-oxo- 1,2,3,4,5,7-hexahydro-6H-pyrazolo[3,4-c] pyridin-6-yl]methyl} benzontrile 375.6 Ex. 94, Scheme1 61

N-{3-[6-(3-cyano benzyl)-3-oxo- 1,3,4,5,6,7-hexahydro-2H-pyrazolo[3,4-c] pyridin-2-yl]phenyl} acetamide 388.5 Ex. 94, Scheme 162

3-{[2-(2-chloro-4-fluoro benzyl)-3-oxo- 1,2,3,4,5,7-hexahydro-6H-pyrazolo[3,4-c] pyridin-6-yl]methyl} benzonitrile 397.9 Ex. 94,Scheme 1 63

2-(4-chlorophenyl)-6- (pyridin-3-ylmethyl)- 1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c] pyridin-3-one 341.9 Ex. 94, Scheme 1 64

3-{[2-(2-morpholin-4- ylethyl)-3-oxo- 1,2,3,4,5,7-hexahydro-6H-pyrazolo[3,4-c] pyridin-6-yl)methyl} benzonitrile 368.7 Ex. 94,Scheme 1 65

N-{3-[6-(3-chloro benzyl)-3-oxo- 1,3,4,5,6,7-hexahydro-2H-pyrazolo[3,4-c] pyridin-2-yl]phenyl} acetamide 398.1 Ex. 94, Scheme 166

2-(1,3-benzodioxol-5- yl)-6-(pyridin-3-yl methyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo [3,4-c]pyridin-3-one 351.4 Ex. 94, Scheme 1 67

2-(4-chlorophenyl)-6- [(6-chloropyridin-3- yl)methyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo [3,4-c]pyridin-3-one 376.4 Ex. 94, Scheme 1 68

2-(4-chlorophenyl)-6-[4- (methylsulfonyl)benzyl]- 1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c] pyridin-3-one 419.1 Ex. 94, Scheme 1 69

2-(1,3-benzodioxol-5- yl)-6-[3-(trifluoro methyl)benzyl]-1,2,4,5,6,7-hexahydro- 3H-pyrazolo[3,4-c] pyridin-3-one 418.5 Ex. 94,Scheme 1 70

2-(1,3-benzodioxol-5- yl)-6-[(6-chloropyridin- 3-yl)methyl]-1,2,4,5,6,7-hexahydro- 3H-pyrazolo[3,4-c] pyridin-3-one 385.9 Ex. 94,Scheme 1 71

6-(3-chloro-4-fluoro benzyl)-2-(1- methylpiperidin-4-yl)-1,2,4,5,6,7-hexahydro- 3H-pyrazolo[3,4-c] pyridin-3-one 380.0 Ex. 94,Scheme 1 72

6-(3-chloro-4-fluoro benzyl)-2-(2-morpholin- 4-ylethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo [3,4-c]pyridin-3-one 395.9 Ex. 94, Scheme 1 73

2-benzyl-6-(3-chloro-4- fluorobenzyl)- 1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c] pyridin-3-one 372.7 Ex. 94, Scheme 1 74

2-(2-morpholin-4-yl ethyl)-6-[3-(trifluoro methyl)benzyl]-1,2,4,5,6,7-hexahydro- 3H-pyrazolo[3,4-c] pyridin-3-one 411.5 Ex. 94,Scheme 1 75

6-(3-chlorobenzyl)-2-(4- methoxybenzyl)- 1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c] pyridin-3-one 384.8 Ex. 94, Scheme 1 76

3-[(2-benzyl-3-oxo- 1,2,3,4,5,7-hexahydro- 6H-pyrazolo[3,4-c]pyridin-6-yl)sulfonyl] benzonitrile 395.8 Ex. 94, Scheme 1 77

2-(4-chlorophenyl)-6- [(4-methylphenyl) sulfonyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo [3,4-c]pyridin-3-one 404.9 Ex. 94, Scheme 1 78

6-(1H-benzimidazol-2- ylmethyl)-2-benzyl- 1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c] pyridin-3-one 360.6 Ex. 94, Scheme 1 79

2-benzyl-6-(pyridin-3- ylsulfonyl)-1,2,4,5,6,7- hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one 371.5 Ex. 94, Scheme 1 80

2-(2-methyl-1,3-benzo thiazol-6-yl)-6-(pyridin- 2-ylmethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo [3,4-c]pyridin-3-one 378.6 Ex. 94, Scheme 1 81

3-{[2-(4-cyanophenyl)- 3-oxo-1,2,3,4,5,7- hexahydro-6H-pyrazolo[3,4-c]pyridin-6-yl] methyl}benzonitrile 356.7 Ex. 94, Scheme 1 82

2-benzyl-6-[4-(methyl sulfonyl)benzyl]- 1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c] pyridin-3-one 398.6 Ex. 94, Scheme 1 83

2-(2-methyl-1,3-benzo thiazol-6-yl)-6-(pyridin- 3-ylmethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo [3,4-c]pyridin-3-one 378.4 Ex. 94, Scheme 1 84

6-(4-chlorobenzyl)-2-(2- morpholin-4-ylethyl)- 1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c] pyridin-3-one 376.8 Ex. 94, Scheme 1 85

3-{6-[(6-chloropyridin- 3-yl)methyl]-3-oxo- 1,3,4,5,6,7-hexahydro-2H-pyrazolo[3,4-c] pyridin-2-yl}benzonitrile 366.9 Ex. 94, Scheme 1 86

2-benzyl-6-[(6-chloro pyridin-3-yl)methyl]- 1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c] pyridin-3-one 355.9 Ex. 94, Scheme 1 87

3-[3-oxo-6-(pyridin-3- ylmethyl)-1,3,4,5,6,7- hexahydro-2H-pyrazolo[3,4-c]pyridin-2-yl] benzonitrile 332.6 Ex. 94, Scheme 1 88

6-(4-chlorobenzyl)-2-(2- methyl-1,3-benzothiazol- 6-yl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo [3,4-c]pyridin-3-one 411.9 Ex. 94, Scheme 1 89

N-{3-[3-oxo-6-(pyridin- 3-ylmethyl)-1,3,4,5,6,7- hexahydro-2H-pyrazolo[3,4-c]pyridin-2-yl] phenyl}acetamide 364.6 Ex. 94, Scheme 1 90

6-(3-chloro-4-fluoro benzyl)-2-(2-methoxy ethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo [3,4-c]pyridin-3-one 340.8 Ex. 94, Scheme 1 91

2-(2-methoxyethyl)-6- (pyridin-3-ylmethyl)- 1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c] pyridin-3-one 289.4 Ex. 94, Scheme 1 92

6-(3,5-dichlorobenzyl)- 2-(2-morpholin-4- ylethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo [3,4-c]pyridin-3-one 412.5 Ex. 94, Scheme 1 93

2-(1-phenylethyl)-6- (pyridin-3-ylmethyl)- 1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c] pyridin-3-one 335.6 Ex. 94, Scheme 1 94

2-(4-chlorophenyl)-6- (pyridin-2-ylmethyl)- 1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c] pyridin-3-one 341.9 Ex. 94, Scheme 1 95

2-(2-chloro-4-fluoro benzyl)-6-(pyridin-3- ylmethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo [3,4-c]pyridin-3-one 373.9 Ex. 94, Scheme 1 96

6-(3-chlorobenzyl)-2- [1,2,4,]triazolo[4,3- b]pyridazin-6-yl-1,2,4,5,6,7-hexahydro- 3H-pyrazolo[3,4-c] pyridin-3-one 382.8 Ex. 94,Scheme 1 97

6-(3-chlorobenzyl)-2-{5- [(4-methylpiperazin-1- yl)sulfonyl]pyridin-2-yl}-1,2,4,5,6,7- hexahydro-3H-pyrazolo [3,4-c]pyridin-3-one 504.1 Ex.94, Scheme 1 98

3-[(2-{5-[(4-methyl piperazin-1-yl)sulfonyl] pyridin-2-yl}-3-oxo-1,2,3,4,5,7-hexahydro- 6H-pyrazolo[3,4-c] pyridin-6-yl)methyl]benzonitrile 494.7 Ex. 94, Scheme 1 99

6-(3-chloro-4-fluoro benzyl)-2-(4-chloro phenyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo [3,4-c]pyridin-3-one 393.4 Ex. 94, Scheme 1 100

2-(2-chloro-4-fluoro benzyl)-6-[(6-chloro pyridin-3-yl)methyl]-1,2,4,5,6,7-hexahydro- 3H-pyrazolo[3,4-c] pyridin-3-one 408.5 Ex. 94,Scheme 1 101

4-{6-[(6-chloropyridin- 3-yl)methyl]-3-oxo- 1,3,4,5,6,7-hexahydro-2H-pyrazolo[3,4-c] pyridin-2-yl}benzonitrile 366.8 Ex. 94, Scheme 1 102

2-(2-chloro-4-fluoro benzyl)-6-[3-(trifluoro methyl)benzyl]-1,2,4,5,6,7-hexahydro- 3H-pyrazolo[3,4-c] pyridin-3-one 440.9 Ex. 94,Scheme 1 103

6-(3-chloro-4-fluoro benzyl)-2-(2-methyl-1,3- benzothiazol-6-yl)-1,2,4,5,6,7-hexahydro- 3H-pyrazolo[3,4-c] pyridin-3-one 429.8 Ex. 94,Scheme 1 104

2-(2-methyl-1,3-benzo thiazol-6-yl)-6-[3- (trifluoromethyl)benzyl]-1,2,4,5,6,7-hexahydro- 3H-pyrazolo[3,4-c] pyridin-3-one 445.6 Ex. 94,Scheme 1 105

2-(2-benzyl-3-oxo- 1,2,3,4,5,7-hexahydro- 6H-pyrazolo[3,4-c]pyridin-6-yl)-N-methyl acetamide 301.4 Ex. 94, Scheme 1 106

3-{[2-(2,3-dihydro-1,4- benzodioxin-6-yl)-3- oxo-1,2,3,4,5,7-hexahydro-6H-pyrazolo [3,4-c]pyridin-6-yl] methyl}benzonitrile 389.5 Ex.94, Scheme 1 107

2-benzyl-6-[(1-methyl- 1H-pyrazol-3-yl) methyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo [3,4-c]pyridin-3-one 324.4 Ex. 94, Scheme 1 108

3-{6-[4-(methylsulfonyl) benzyl]-3-oxo- 1,3,4,5,6,7-hexahydro-2H-pyrazolo[3,4-c] pyridin-2-yl}benzonitrile 409.5 Ex. 94, Scheme 1 109

3-[6-(3-chloro-4-fluoro benzyl)-3-oxo- 1,3,4,5,6,7-hexahydro-2H-pyrazolo[3,4-c] pyridin-2-yl]benzonitrile 383.8 Ex. 94, Scheme 1 110

6-[(6-chloropyridin-3-yl) methyl]-2-(2-methyl-1,3- benzothiazol-6-yl)-1,2,4,5,6,7-hexahydro- 3H-pyrazolo[3,4-c] pyridin-3-one 412.9 Ex. 94,Scheme 1 111

3-{3-oxo-6-[3-(trifluoro methyl)benzyl]- 1,3,4,5,6,7-hexahydro-2H-pyrazolo[3,4-c] pyridin-2-yl} benzonitrile 398.4 Ex. 94, Scheme 1 112

6-[(6-chloropyridin-3- yl)methyl]-2-(2-fluoro phenyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo [3,4-c]pyridin-3-one 359.8 Ex. 94, Scheme 1 113

4-[3-oxo-6-(pyridin-3- ylmethyl)-1,3,4,5,6,7- hexahydro-2H-pyrazolo[3,4-c]pyridin-2-yl] benzonitrile 332.4 Ex. 94, Scheme 1 114

N-(3-{6-[(6-chloro pyridin-3-yl)methyl]-3- oxo-1,3,4,5,6,7-hexahydro-2H-pyrazolo [3,4-c]pyridin-2-yl} phenyl)acetamide 398.9 Ex.94, Scheme 1 115

6-(3-chlorobenzyl)-2-[4- (trifluoromethyl)phenyl]-1,2,4,5,6,7-hexahydro- 3H-pyrazolo[3,4- c]pyridin-3-one 408.8 Ex. 94,Scheme 1 116

6-(3-chlorobenzyl)-2-(4- chloro-2-fluorophenyl)- 1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c] pyridin-3-one 393.3 Ex. 94, Scheme 1 117

6-(pyridin-3-ylmethyl)- 2-[4-(trifluoro methyl) phenyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo [3,4-c]pyridin-3-one 375.4 Ex. 94, Scheme 1 118

2-(4-methoxyphenyl)-6- (pyridin-3-ylmethyl)- 1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c] pyridin-3-one 337.4 Ex. 94, Scheme 1 119

2-[3-(benzyloxy) phenyl]-6-[(4-methyl phenyl)sulfonyl]-1,2,4,5,6,7-hexahydro- 3H-pyrazolo[3,4-c] pyridin-3-one 476.5 Ex. 94,Scheme 1 120

N-{4-[(2-benzyl-3-oxo- 1,2,3,4,5,7-hexahydro- 6H-pyrazolo[3,4-c]pyridin-6-yl)methyl] phenyl}acetamide 377.5 Ex. 94, Scheme 1 121

6-(3-chlorobenzyl)-2-(3- fluorobenzyl)- 1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c] pyridin-3-one 372.8 Ex. 94, Scheme 1 122

6-(3-chlorobenzyl)-2-(4- fluorobenzyl)- 1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c] pyridin-3-one 372.8 Ex. 94, Scheme 1 123

6-(3-chlorobenzyl)-2-[2- (dimethylamino)benzyl]- 1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c] pyridin-3-one 370.9 Ex. 94, Scheme 1 124

5-[(2-benzyl-3-oxo- 1,2,3,4,5,7-hexahydro- 6H-pyrazolo[3,4-c]pyridin-6-yl)methyl]-2- fluorobenzonitrile 363.4 Ex. 94, Scheme 1 125

2-benzyl-6-(quinolin-2- ylmethyl)-1,2,4,5,6,7- hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one 371.5 Ex. 94, Scheme 1 126

3-{[2-(2-methyl-1,3- benzothiazol-6-yl)-3- oxo-1,2,3,4,5,7-hexahydro-6H-pyrazolo [3,4-c]pyridin-6-yl] methyl}benzonitrile 355.8 Ex.94, Scheme 1 127

2-benzyl-6-[(6-chloro pyridin-2-yl)methyl]- 1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c] pyridin-3-one 355.8 Ex. 94, Scheme 1 128

2-benzyl-6-(3-methoxy benzyl)-1,2,4,5,6,7- hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one 350.4 Ex. 94, Scheme 1 129

2-benzyl-6-(4-methoxy benzyl)-1,2,4,5,6,7- hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one 350.4 Ex. 94, Scheme 1 130

2-benzyl-6-[(5-methyl isoxazol-3-yl)methyl]- 1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c] pyridin-3-one 325.4 Ex. 94, Scheme 1 131

6-(1,3-benzothiazol-2-yl methyl)-2-benzyl- 1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c] pyridin-3-one 377.5 Ex. 94, Scheme 1 132

3-[6-(4-chlorobenzyl)-3- oxo-1,3,4,5,6,7- hexahydro-2H-pyrazolo[3,4-c]pyridin- 2-yl]propanenitrile 317.8 Ex. 94, Scheme 1 133

2-benzyl-6-[(3-fluoro phenyl)sulfonyl]- 1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c] pyridin-3-one 388.4 Ex. 94, Scheme 1 134

2-benzyl-6-[(3-methoxy phenyl)sulfonyl]- 1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c] pyridin-3-one 400.5 Ex. 94, Scheme 1 135

2-benzyl-6-[(3-chloro phenyl)sulfonyl]- 1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c] pyridin-3-one 404.9 Ex. 94, Scheme 1 136

2-benzyl-6-[(4-methoxy phenyl)sulfonyl]- 1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c] pyridin-3-one 400.5 Ex. 94, Scheme 1 137

2-benzyl-6-[(4-chloro phenyl)sulfonyl]- 1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c] pyridin-3-one 404.9 Ex. 94, Scheme 1 138

2-benzyl-6-[(4- fluorophenyl)sulfonyl]- 1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4- c]pyridin-3-one 388.4 Ex. 94, Scheme 1 139

2-benzyl-6-[(4-methyl- 3,4-dihydro-2H-1,4- benzoxazin-6-yl)sulfonyl]-1,2,4,5,6,7- hexahydro-3H-pyrazolo [3,4-c]pyridin-3-one 441.5Ex. 94, Scheme 1 140

2-benzyl-6-(quinolin-8- ylsulfonyl)-1,2,4,5,6,7- hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one 421.5 Ex. 94, Scheme 1 141

3-{[3-oxo-2-(2-phenyl ethyl)-1,2,3,4,5,7- hexahydro-6H-pyrazolo[3,4-c]pyridin-6-yl] methyl}benzonitrile 359.4 Ex. 94, Scheme 1 142

3-{[2-(4-methoxy phenyl)-3-oxo- 2,3,3a,4,5,7-hexahydro-6H-pyrazolo[3,4-c] pyridin-6-yl]methyl} benzonitrile 361.4 Ex. 94,Scheme 1 143

6-[(4- methylphenyl)sulfonyl]- 2-(2-phenoxyethyl)-1,2,4,5,6,7-hexahydro- 3H-pyrazolo[3,4- c]pyridin-3-one 414.5 Ex. 94,Scheme 1 144

6-(3-chlorobenzyl)-2- (pyridin-4-ylmethyl)- 1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c] pyridin-3-one 354.8 Ex. 94, Scheme 1 145

6-[(4-methyl phenyl)sulfonyl]-2- phenyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [3,4-c]pyridin-3-one 670.4 Ex. 94, Scheme 1 146

2-(diphenylmethyl)-6- (pyridin-3-ylmethyl)- 1,2,4,5,67-hexahydro-3H-pyrazolo[3,4- c]pyridin-3-one 397.4 Ex. 94, Scheme 1 147

6-[(4-methyl phenyl)sulfonyl]-2-(2- morpholin-4-ylethyl)-1,2,4,5,6,7-hexahydro- 3H-pyrazolo[3,4-c] pyridin-3-one 407.5 Ex. 94,Scheme 1 148

6-[(4-methyl phenyl)sulfonyl]-2- (pyridin-2-ylmethyl)-1,2,4,5,6,7-hexahydro- 3H-pyrazolo[3,4-c] pyridin-3-one 385.5 Ex. 94,Scheme 1 149

6-[(4-methyl phenyl)sulfonyl]-2-(1- methylpiperidin-4-yl)-1,2,4,5,6,7-hexahydro- 3H-pyrazolo[3,4-c] pyridin-3-one 391.5 Ex. 94,Scheme 1 150

2-(imidazo[1,2-a] pyridin-2-ylmethyl)-6- [(4-methyl phenyl)sulfonyl]-1,2,4,5,6,7- hexahydro-3H-pyrazolo [3,4-c]pyridin-3-one 424.5Ex. 94, Scheme 1 151

3-{6-[(4-methyl phenyl) sulfonyl]-3-oxo- 1,3,4,5,6,7-hexahydro-2H-pyrazolo[3,4-c] pyridin-2-yl} propanenitrile 347.5 Ex. 94, Scheme 1152

2-[2-(dimethyl amino) benzyl]-6-[(4-methyl phenyl)sulfonyl]-1,2,4,5,6,7-hexahydro- 3H-pyrazolo[3,4-c] pyridin-3-one 427.5 Ex. 94,Scheme 1 153

6-[(4-methylphenyl) sulfonyl]-2-(pyridin-4- ylmethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo [3,4-c]pyridin-3-one 385.5 Ex. 94, Scheme 1 154

2-[2-(dimethyl amino) ethyl]-6-[(4-methyl phenyl)sulfonyl]-1,2,4,5,6,7-hexahydro- 3H-pyrazolo[3,4-c] pyridin-3-one 365.5 Ex. 94,Scheme 1 155

2-{5-[(4-methyl piperazin-1-yl)sulfonyl] pyridin-2-yl}-6-(methylsulfonyl)- 1,2,4,5,6,7-hexahydro- 3H-pyrazolo[3,4-c]pyridin-3-one 457.5 Ex. 94, Scheme 1 156

6-[(3-chloro-4-fluoro phenyl)sulfonyl]-2- (imidazo[1,2-a]pyridin-2-ylmethyl)-1,2,4,5,6,7- hexahydro-3H-pyrazolo [3,4-c]pyridin-3-one462.9 Ex. 94, Scheme 1 157

6-[(4-methylphenyl) sulfonyl]-2-quinoxazolin- 2-yl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [3,4-c]pyridin-3-one 422.5 Ex. 94, Scheme 1 158

6-[(4- methylphenyl)sulfonyl]- 2-(pyridin-3-ylmethyl)-1,2,4,5,6,7-hexahydro- 3H-pyrazolo[3,4- c]pyridin-3-one 385.5 Ex. 94,Scheme 1 159

6-[(4-methylphenyl) sulfonyl]-2-pyridin-2-yl- 1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c] pyridin-3-one 371.4 Ex. 94, Scheme 1 160

6-[(3,4-dichloro phenyl)sulfonyl]-2- (imidazo[1,2-a]pyridin-2-ylmethyl)-1,2,4,5,6,7- hexahydro-3H-pyrazolo [3,4-c]pyridin-3-one479.4 Ex. 94, Scheme 1 161

2-(7-chloroquinolin-4- yl)-6-[(4-methyl phenyl)sulfonyl]-1,2,4,5,6,7-hexahydro- 3H-pyrazolo[3,4-c] pyridin-3-one 455.9 Ex. 94,Scheme 1 162

N-(3-{6-[(4-methyl phenyl)sulfonyl]-3-oxo- 1,3,4,5,6,7-hexahydro-2H-pyrazolo[3,4-c] pyridin-2-yl}phenyl) acetamide 427.5 Ex. 94, Scheme 1163

6-(biphenyl-4-yl sulfonyl)-2-(imidazo [1,2-a]pyridin-2-ylmethyl)-1,2,4,5,6,7- hexahydro-3H-pyrazolo [3,4-c]pyridin-3-one 486.6Ex. 94, Scheme 1 164

2-(imidazo[1,2-a] pyridin-2-ylmethyl)-6- {[3-(trifluoromethyl)phenyl]sulfonyl}- 1,2,4,5,6,7-hexahydro- 3H-pyrazolo[3,4-c]pyridin-3-one 478.5 Ex. 94, Scheme 1 165

2-benzyl-6-(phenyl sulfonyl)-1,2,4,5,6,7- hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one 370.5 Ex. 94, Scheme 1 166

2-(2-morpholin-4-yl ethyl)-6-(phenyl sulfonyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo [3,4-c]pyridin-3-one 393.5 Ex. 94, Scheme 1 167

6-[(4- chlorophenyl)sulfonyl]- 2-phenyl-1,2,4,5,6,7- hexahydro-3H-pyrazolo[3,4-c]pyridin- 3-one 390.9 Ex. 94, Scheme 1 168

2-benzyl-6-[(4-tert- butylphenyl)sulfonyl]- 1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4- c]pyridin-3-one 426.7 Ex. 94, Scheme 1 169

2-(1-benzylpiperidin-4- yl)-6-[(4- methylphenyl)sulfonyl]-1,2,4,5,6,7-hexahydro- 3H-pyrazolo[3,4- c]pyridin-3-one 467.8 Ex. 94,Scheme 1 170

6-[(4- chlorophenyl)sulfonyl]- 2-(2-morpholin-4- ylethyl)-1,2,4,5,6,7-hexahydro-3H- pyrazolo[3,4-c]pyridin- 3-one 428.0 Ex. 94, Scheme 1 171

2-[2-fluoro-4- (methylsulfonyl)phenyl]- 6-[(4- methylphenyl)sulfonyl]-1,2,4,5,6,7-hexahydro- 3H-pyrazolo[3,4- c]pyridin-3-one 466.6 Ex. 94,Scheme 1

Example 2 Measurement of Levels of Reactive Oxygen Species in DifferentCell Cultures

The activity of the compounds according to the invention may be testedfor their activity in the inhibition or reduction of formation ofreactive oxygen species (ROS) from oxygen in cells. The activity of thecompounds is tested in the following cell cultures by differenttechniques such as nitroblue tetrazolium, Amplex Red, Chemiluminescence(Luminol) and 2′,7′-dichlorodihydrofluorescein diacetate (H₂DCF-DA)according to the protocols detailed below.

Human Microglia Cell Line

Human microglia cell line (HMC3, human microglia clone 3) (Janabi etal., 1995, Neurosci. Lett. 195:105) were cultured in MEM (Eagle'sminimum essential medium) containing 10% FBS with 50 U/ml penicillin Gsodium 50 μg/ml streptomycin sulfate, and incubated at 37° C. for 24hours. IFN-γ (human IFN-γ, Roche. 11 040 596 001) was added to theculture medium for a final concentration of 10 ng/ml 24 h, beforedetection of O₂ formation.

Human Umbilical Vein Endothelial Cells (HUVEC)

HUVEC are cultured in endothelial basal medium supplemented withhydrocortisone (1 μg/mL, CalbioChem), bovine brain extract (12 μg/mL),gentamicin (50 μg/mL, CalbioChem), amphotericin B (50 ng/mL, CalBioChemEGF (10 ng/mL, and 10% FCS until the fourth passage. When the fifthpassage was started, cells were cultured with a lower concentration ofFCS (2%) in the absence of EGF, if not indicated otherwise. Allexperiments were done with cells of the fifth passage. The cells wereincubated with OxLDL (oxidized low-density lipoprotein) or its buffer ascontrol for 24 h, before detection of O₂ ⁻ formation.

HL-60 Cells

Human acute myeloid leukemia cell line HL-60 was cultured in RPMI 1640(Invitrogen) supplemented with 10% heat-inactivated calf serum, 2 mMglutamine, 100 U/mL penicillin (Sigma), and 100 μg streptomycin (Sigma)at 37° C. under a humidified atmosphere of 5% CO₂. HL60 differentiationto the neutrophil phenotype was triggered by adding Me₂SO (finalconcentration 1.25% v/v for 6 days) to the culture medium.

1. Nitroblue Tetrazolium (NBT)

Intracellular and extracellular superoxide was measured by acolorimetric technique using a quantitative nitroblue tetrazolium (NBT)test. SOD-inhibitable conversion of NBT to formazan, a fine blueprecipitate, in the presence of superoxide anion was measured usingFluostar Optima spectrometer (BMG labtech). Following incubation withappropriate stimuli, cells were trypsinized (1× Trypsin-EDTA), collectedby centrifugation, and washed with PBS to remove medium. 5×10⁵ cellswere plated on 48-well plates and incubated in Hank's balanced saltsolution containing 0.5 mg/mL NBT with or without 800 U/mL SOD in thepresence or absence of compounds according to the invention. As acontrol, DPI was included at a final concentration of 10 μM. After 2.5h, cells were fixed and washed with methanol to remove non reduced NBT.The reduced formazan was then dissolved in 230 μl of 2M potassiumhydroxide and in 280 μl of dimethylsulfoxide. The absorption wasmeasured at 630 nm. For calculation, the absorbance at 630 nm wasnormalized for each individual well. The mean of the four blank valueswas subtracted from each corrected value for each time point. NOXactivities were expressed as % of the activity in control cells.Residual activity of DPI-treated cells was usually <10%.

2. Amplex Red

Extracellular hydrogen peroxide was measured using Amplex UltraRed(Molecular Probes). Cells were trypsinized (1× Trypsin-EDTA), collectedby centrifugation, and resuspended in HBSS supplemented with 1% glucose.Cells were seeded into black 96-well plates at a density of 50′000 cellsin 200 μl testing buffer (HBSS 1% glucose containing 0.005 U/mLhorseradish peroxidase (Roche) and 50 μM Amplex Red in the presence orabsence of compounds according to the invention. As a control, DPI wasincluded at a final concentration of 10 μM The plates were placed in thefluorescent Optima Fluorescent plate reader and kept at 37° C. during 20min. Fluorescence was measured for 15 min hours with excitation andemission wavelengths of 544 nm and 590 nm respectively. NOX activitieswere expressed as % of the activity in control cells. Residual activityof DPI-treated cells was usually <10%.

The Table 2 below summarizes the percentage of inhibition of NOXactivity as measured by Amplex Red using DMSO-differentiated HL60 cellsas described above:

TABLE 2 Compound n° Inhibition (%)  (1) 83  (2) 64  (3) 65  (5) 72  (8)62  (9) 73 (12) 65 (13) 61 (14) 60 (16) 75 (20) 78 (26) 70 (28) 79 (34)64 (35) 78 (39) 78 (40) 70 (45) 75 (46) 75 (47) 74 (48) 68 (59) 66 (65)60 (76) 71 (78) 70 (79) 69 (80) 66 (93) 79 (100)  65 (105)  65 (106)  63(107)  67 (120)  63 (123)  70 (130)  77 (131)  76 (132)  76 (139)  75(140)  72 (146)  81 (150)  74 (151)  69 (152)  78 (154)  51 (168)  70

The Table 3 below summarizes the IC₅₀ of NOX activity as measured byAmplex Red using DMSO-differentiated HL60 cells as described above:

TABLE 3 Compound n° IC₅₀ (μM)  (1) <5  (2) <5  (5) <5  (7) <5  (8) <5(12) <5 (47) <5 (79) <5 (120)  <5 (123)  <53. Chemiluminescence (Luminol)

ROS was measured using the chemiluminescent probe luminol. Cells werecultured and plated as for Amplex Red except that the Amplex Red agentwas replaced by 10 μg/mL luminol (Sigma 09235). Light emission wasrecorded continuously at 37° C. for 60 minutes using the luminescencefunction of the FluoStar Optima fluorescent plate reader. The mean ofthe four blank values was subtracted from each corrected value for eachtime point. NOX activities were expressed as % of the activity incontrol cells. Residual activity of DPI-treated cells was usually <10%.

4. 2′,7′-dichlorodihydrofluorescein diacetate (H₂DCF-DA)

HUVEC were plated on coverslips and made quiescent overnight in 0.5% BSAbefore stimulation with TGF-β. Cells were loaded for 10 minutes with 5μM CM-H2DCFDA in phenol-red-free medium in the dark and then treatedwith TGF-β (R&D Systems) in the presence or absence of compoundsaccording to the invention. Cells were then visualized byimmunofluorescence microscopy after fixation and staining of the nucleiwith DAPI or examined live using confocal microscopy. DCF fluorescencewas visualized at an excitation wavelength of 488 nm and emission at 515to 540 nm. To avoid photo-oxidation of the indicator dye, images werecollected with a single rapid scan using identical parameters for allsamples. For calculation, the absorbance at 540 nm was normalized toabsorbance at 540 nm for each individual well. The mean of the fourblank values was subtracted from each corrected value for each timepoint. NOX activities were expressed as % of the activity in controlcells. Residual activity of DPI-treated cells was usually <10%.

Example 3 Blood Pressure Measurement in Spontaneous Hypertensive Rats(SHR)

In order to test the ability of compounds according to the invention totreat hypertension, the following assay is carried out.

SHR at 11 weeks of age with systolic blood pressure above 170 mmHg areused. Compound according to the invention are administered orally torats at a dose of about 3, 10, 30 and 100 mg/kg between 10:00 and 12:00h. Mean, systolic and diastolic blood pressure and heart rate aremonitored 2, 4, 6, 8 and 24 hours after the first administration of acompound according to the invention in order to perform a kineticanalysis over one day. After that, blood pressure is monitored every twodays for two weeks, in the morning at 24 h time point and at thehalf-life of the compound.

After the last injection, a 24 hour time point is monitored. The animalsare controlled for an additional week without treatment in order tomonitor the compound withdrawal. The animals are treated once a day fora period of two weeks by gavage with a special needle adapted for gavageat 5 ml/kg. Before using the animals, they are acclimated for two daysand further trained during one week. The blood pressure is measured inawaken rats by tail-cuff plethysmography (Codas 6, Kent). Animals areincluded into groups after training for several days and if SBPvariability was ≦40 mm Hg, i.e. +/−20 mm Hg. Baseline measurements wereperformed at least on two days before the experiment. Before thebeginning of the experiment, animals are randomized in order toconstitute homogeneous groups.

Example 4 Bleomycine-Induced Lung Injury in Mice

In order to test the ability of compounds according to the invention toprevent or treat respiratory disorder or disease, the following assay iscarried out.

In order to produce pulmonary lesion which are comparable to those inrespiratory disorder or disease such as idiopathic pulmonary fibrosis,animals receive endotracheally a single sublethal dose of bleomycine(BLM) (2.5 U/kg body weight dissolved in 0.25 ml of 0.9% NaCl). Controlanimals are subjected to the same protocol but received the same volumeof intratracheal saline instead of BLM. Tracheal instillation is carriedout under ketamin (80 mg/kg of body weight, i.p.) and xylazine (20 mg/kgde body weight, i.p.) anesthesia. 2 weeks days after endotracheal BLM orsaline, the animals are killed by a lethal injection of sodiumpentobarbital followed by exsanguination of abdominal aorta.Bronchoalveolar lavage is performed and lungs are weighed and processedseparately for biochemical (homogenate right lung, n=10) andhistological (left lung, n=10) studies as indicated below. The animalsare randomly divided into four groups: control-saline (n=8) andcontrol+BLM (n=10); Compound Dose 1+BLM (n=10) and Compound Dose 2+BLM(N=10). Treatments vehicle or compounds are administered for 2 weeks.

Mice are treated by daily oral administration of compound according tothe invention or saline/control starting on day 0 for two weeks. Wholelung accumulation of acid-soluble collagen is analyzed by Sircol assay.

Example 5 Animal Models of Cancer

In order to test the ability of compounds according to the invention totreat cancers, in particular to reduce tumour growth and/orangiogenesis, the following assays are carried out.

In Vivo Angiogenesis Assay

7 to 10 weeks old C57BL6/J females are injected subcutaneously with 400μl of Matrigel growth factor reduced complemented with 500 ng/ml ofangiogenic factor (b-FGF or VEGF). One week after the graft, mice arescanned using MicroCT (Skyscan). Mice are injected retro-orbitally witha tracer (400 μl iodated liposomes) to visualize the vessel density.Scan picture are then reconstituted with Recon program and the densityof grey in the plug is counted in all the slide of the plug. Compoundsof the invention are administered per oral route at the appropriatedoses 1 and 2, once-a-day for 10 days. Results are expressed in greydensity, which is correlated to vessel density. Matrigel plug are alsofrozen and stained for CD31 to visualize vessels.

Tumor Growth Assay

5·10⁵ Lewis Lung Carcinoma cells (LLC1) are injected subcutaneously inthe back of mice. Mice are treated with a compound according to theinvention at 40 mg/kg everyday per os. When the control tumor reachesabout 1 cm length, mice are sacrificed and tumors are recovered, weightand frozen. For therapeutic assay, mice are injected with LLC1 cellssince tumors have grown about 0.5 cm mice are treated and tumor size isassessed every day. After sacrifice, tumour and frozen and sections oftumors are stained with anti-CD31 antibody and KOS level is analyzed.

The invention claimed is:
 1. A pyrazolo piperidine compound according to Formula (I):

wherein R¹ is selected from H; optionally substituted alkoxycarbonyl; optionally substituted C₁-C₆ alkyl; optionally substituted C₂-C₆ alkenyl; optionally substituted C₂-C₆ alkynyl; optionally substituted alkoxy; optionally substituted alkoxy C₁-C₆ alkyl; optionally substituted aminoalkyl; optionally substituted acyl; optionally substituted aryl; optionally substituted C₁-C₆ alkyl aryl; optionally substituted aryl C₁-C₆ alkyl; optionally substituted heteroaryl; optionally substituted C₁-C₆ alkyl heteroaryl; optionally substituted heteroaryl C₁-C₆ alkyl; optionally substituted C₂-C₆ alkenyl aryl; optionally substituted aryl C₂-C₆ alkenyl; optionally substituted C₂-C₆ alkenyl heteroaryl; optionally substituted heteroaryl C₂-C₆ alkenyl; optionally substituted C₃-C₈-cycloalkyl; optionally substituted heterocycloalkyl; optionally substituted C₁-C₆ alkyl C₃-C₈-cycloalkyl; optionally substituted C₃-C₈-cycloalkyl C₁-C₆ alkyl; optionally substituted C₁-C₆ alkyl heterocycloalkyl or optionally substituted heterocycloalkyl C₁-C₆ alkyl; R² is selected from H; optionally substituted C₁-C₆ alkyl; optionally substituted C₂-C₆ alkenyl; optionally substituted C₂-C₆ alkynyl; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted C₃-C₈-cycloalkyl; optionally substituted heterocycloalkyl; optionally substituted C₃-C₈-cycloalkyl C₁-C₆ alkyl; optionally substituted heterocycloalkyl C₁-C₆ alkyl; optionally substituted aryl C₁-C₆ alkyl or optionally substituted heteroaryl C₁-C₆ alkyl; R³ is selected from —S(O)—R⁴, —S(O)₂—R⁴, optionally substituted C₃-C₈-cycloalkyl, optionally substituted heterocycloalkyl or —CR⁵R⁶R⁷; R⁴ is selected from H; optionally substituted amino; optionally substituted C₁-C₆ alkyl; optionally substituted C₂-C₆ alkenyl; optionally substituted C₂-C₆ alkynyl; optionally substituted alkoxy; optionally substituted alkoxy C₁-C₆ alkyl; optionally substituted acyl; optionally substituted aryl; optionally substituted C₁-C₆ alkyl aryl; optionally substituted aryl C₁-C₆ alkyl; optionally substituted heteroaryl; optionally substituted C₁-C₆ alkyl heteroaryl; optionally substituted heteroaryl C₁-C₆ alkyl; optionally substituted C₂-C₆ alkenyl aryl; optionally substituted aryl C₂-C₆ alkenyl; optionally substituted C₂-C₆ alkenyl heteroaryl; optionally substituted heteroaryl C₂-C₆ alkenyl; optionally substituted C₃-C₈-cycloalkyl; optionally substituted heterocycloalkyl; optionally substituted C₁-C₆ alkyl C₃-C₈-cycloalkyl; optionally substituted C₃-C₈-cycloalkyl C₁-C₆ alkyl; optionally substituted C₁-C₆ alkyl heterocycloalkyl or optionally substituted heterocycloalkyl C₁-C₆ alkyl; R⁵ is selected from H or —CR⁸R⁹R¹⁰; R⁶ is selected from H or —CR¹¹R¹²R¹³; R⁷ is selected from H, —CR¹⁴R¹⁵R¹⁶ or —C(O)—R¹⁷; R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are independently selected from H; halogen; optionally substituted amino; optionally substituted acyl; optionally substituted C₁-C₆ alkyl; optionally substituted C₂-C₆ alkenyl; optionally substituted C₂-C₆ alkynyl; optionally substituted aryl; optionally substituted C₁-C₆ alkyl aryl; optionally substituted aryl C₁-C₆ alkyl; optionally substituted heteroaryl; optionally substituted C₁-C₆ alkyl heteroaryl; optionally substituted heteroaryl C₁-C₆ alkyl; optionally substituted C₂-C₆ alkenyl aryl; optionally substituted aryl C₂-C₆ alkenyl; optionally substituted C₂-C₆ alkenyl heteroaryl; optionally substituted heteroaryl C₂-C₆ alkenyl; optionally substituted C₃-C₈-cycloalkyl; optionally substituted heterocycloalkyl; optionally substituted C₁-C₆ alkyl C₃-C₈-cycloalkyl; optionally substituted C₃-C₈-cycloalkyl C₁-C₆ alkyl; optionally substituted C₁-C₆ alkyl heterocycloalkyl or optionally substituted heterocycloalkyl C₁-C₆ alkyl; —CR⁸R⁹R¹⁰, —CR¹¹R¹²R¹³ or —CR¹⁴R¹⁵R¹⁶ can independently form an optionally substituted ring selected from an optionally substituted aryl; an optionally substituted heteroaryl; an optionally substituted C₃-C₈-cycloalkyl or an optionally substituted heterocycloalkyl; or a tautomer, a geometrical isomer, an optically active form, or a pharmaceutically active salt thereof, with the proviso that the compound is not selected from the group consisting of: 6-methyl-2-phenyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 6-benzyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; and 6-benzyl-2,3a,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one.
 2. The compound according to claim 1, wherein R¹ is selected from optionally substituted aryl or optionally substituted heteroaryl.
 3. The compound according to claim 1, wherein R¹ is selected from optionally substituted C₁-C₆ alkyl; optionally substituted C₂-C₆ alkenyl; or optionally substituted C₂-C₆ alkynyl.
 4. The compound according to claim 1, wherein R¹ is selected from optionally substituted aryl C₁-C₆ alkyl or optionally substituted heteroaryl C₁-C₆ alkyl.
 5. The compound according to claim 1, wherein R¹ is optionally substituted heterocycloalkyl.
 6. The compound according to claim 1, wherein R¹ is optionally substituted heterocycloalkyl C₁-C₆ alkyl.
 7. The compound according to claim 1, wherein R¹ is optionally substituted alkoxy C₁-C₆ alkyl.
 8. The compound according to claim 1, wherein R² is H.
 9. The compound according to claim 1, wherein R³ is —CR⁵R⁶R⁷.
 10. The compound according to claim 1, wherein R³ is —CR⁵R⁶R⁷; R⁵ and R⁶ are independently selected from H or optionally substituted C₁-C₆ alkyl; and R⁷ is —CR¹⁴R¹⁵R¹⁶.
 11. The compound according to claim 1, wherein R³ is S(O)₂—R⁴.
 12. The compound according to claim 11, wherein R³ is S(O)₂—R⁴ and R⁴ is selected from optionally substituted C₁-C₆ alkyl; optionally substituted C₂-C₆ alkenyl or optionally substituted C₂-C₆ alkynyl.
 13. The compound according to claim 11, wherein R³ is S(O)₂—R⁴ and R⁴ is selected from optionally substituted aryl or optionally substituted heteroaryl.
 14. The compound according to claim 1 selected from the group consisting of: 6-benzyl-2-(2-chloro-4-fluorophenyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 6-benzyl-2-[3-(benzyloxy)phenyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 6-benzyl-2-(4-chlorobenzyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 6-benzyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 2,6-dibenzyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 6-benzyl-2-(3-methoxyphenyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 6-benzyl-2-(3-chlorophenyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 6-benzyl-2-phenyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 6-benzyl-2-methyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 6-(3-chlorobenzyl)-2-(3-methoxyphenyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 6-(3,5-dimethoxybenzyl)-2-(3-methoxyphenyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 6-benzyl-2-(2-methoxyphenyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 6-(4-chlorobenzyl)-2-(3-methoxyphenyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 6-(2,4-dichlorobenzyl)-2-(3-methoxyphenyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 2-benzyl-6-(3-chlorobenzyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 6-(3-chlorobenzyl)-2-(2-hydroxyethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 6-(3-chlorobenzyl)-2-(3-methoxybenzyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 6-(3-chlorobenzyl)-2-(2-methoxybenzyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 6-(3-chlorobenzyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 6-(3-chlorobenzyl)-2-(1-methylpiperidin-4-yl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 2-benzyl-6-(4-chlorobenzyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 6-(4-chlorobenzyl)-2-(2-methoxybenzyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 6-(4-chlorobenzyl)-2-(3-methoxybenzyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 6-(4-chlorobenzyl)-2-(2-hydroxyethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 2-(3-methoxyphenyl)-6-(1-phenylethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 6-(3-chlorobenzyl)-2-(2-methoxyethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 6-(4-chlorobenzyl)-2-(2-methoxyethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 2-(1,3-benzodioxol-5-yl)-6-(4-chlorobenzyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 2-(1,3-benzodioxol-5-yl)-6-(3-chlorobenzyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 4-[6-(3-chlorobenzyl)-3-oxo-1,3,4,5,6,7-hexahydro-2H-pyrazolo[3,4-c]pyridin-2-yl]benzonitrile; 6-(3-chlorobenzyl)-2-(4-chlorophenyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 6-(3-chlorobenzyl)-2-(2-morpholin-4-ylethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 3-[(2-benzyl-3-oxo-1,2,3,4,5,7-hexahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methyl]benzonitrile; 6-(3-chlorobenzyl)-2-(2-piperidin-1-ylethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 3-{[2-(1,3-benzodioxol-5-yl)-3-oxo-1,2,3,4,5,7-hexahydro-6H-pyrazolo[3,4-c]pyridin-6-yl]methyl}benzonitrile; 3-[6-(3-chlorobenzyl)-3-oxo-1,3,4,5,6,7-hexahydro-2H-pyrazolo[3,4-c]pyridin-2-yl]benzonitrile; 3-{[2-(3-methoxyphenyl)-3-oxo-1,2,3,4,5,7-hexahydro-6H-pyrazolo[3,4-c]pyridin-6-yl]methyl}benzonitrile; 3-{[2-(2-methoxyethyl)-3-oxo-1,2,3,4,5,7-hexahydro-6H-pyrazolo[3,4-c]pyridin-6-yl]methyl}benzonitrile; 6-(3-chlorobenzyl)-2-[2-(4-chlorophenoxy)ethyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 2-benzyl-6-[(4-methylphenyl)sulfonyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 6-(2-methoxybenzyl)-2-(3-methoxyphenyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 6-(4-chlorobenzyl)-2-(1-methylpiperidin-4-yl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 3-{[2-(2-hydroxyethyl)-3-oxo-1,2,3,4,5,7-hexahydro-6H-pyrazolo[3,4-c]pyridin-6-yl]methyl}benzonitrile; 2-benzyl-6-(pyridin-3-ylmethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 2-benzyl-6-(pyridin-2-ylmethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 2-(1-benzylpiperidin-4-yl)-6-(3-chlorobenzyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 2-benzyl-6-[(2-methyl-1,3-thiazol-4-yl)methyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 2-benzyl-6-(methylsulfonyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 6-(3-chlorobenzyl)-2-(3-hydroxybenzyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 6-(3-chlorobenzyl)-2-(pyridin-3-ylmethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 6-(3-chlorobenzyl)-2-(1-phenylethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 3-{[2-(4-chlorophenyl)-3-oxo-1,2,3,4,5,7-hexahydro-6H-pyrazolo[3,4-c]pyridin-6-yl]methyl}benzonitrile; 3-{[2-(1-methylpiperidin-4-yl)-3-oxo-1,2,3,4,5,7-hexahydro-6H-pyrazolo[3,4-c]pyridin-6-yl]methyl}benzonitrile; 6-(3-chlorobenzyl)-2-(4-methoxyphenyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 2-benzyl-6-(2-methoxybenzyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 6-(4-chlorobenzyl)-2-(2-chloro-4-fluorobenzyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 6-(3-chlorobenzyl)-2-(2-chloro-4-fluorobenzyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 3-[6-(3-cyanobenzyl)-3-oxo-1,3,4,5,6,7-hexahydro-2H-pyrazolo[3,4-c]pyridin-2-yl]benzonitrile; 6-(4-chlorobenzyl)-2-(2-piperidin-1-ylethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 3-{[2-(3-methoxybenzyl)-3-oxo-1,2,3,4,5,7-hexahydro-6H-pyrazolo[3,4-c]pyridin-6-yl]methyl}benzonitrile; N-{3-[6-(3-cyanobenzyl)-3-oxo-1,3,4,5,6,7-hexahydro-2H-pyrazolo[3,4-c]pyridin-2-yl]phenyl}acetamide; 3-{[2-(2-chloro-4-fluorobenzyl)-3-oxo-1,2,3,4,5,7-hexahydro-6H-pyrazolo[3,4-c]pyridin-6-yl]methyl}benzonitrile; 2-(4-chlorophenyl)-6-(pyridin-3-ylmethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 3-{[2-(2-morpholin-4-ylethyl)-3-oxo-1,2,3,4,5,7-hexahydro-6H-pyrazolo[3,4-c]pyridin-6-yl]methyl}benzonitrile; N-{3-[6-(3-chlorobenzyl)-3-oxo-1,3,4,5,6,7-hexahydro-2H-pyrazolo[3,4-c]pyridin-2-yl]phenyl}acetamide; 2-(1,3-benzodioxol-5-yl)-6-(pyridin-3-ylmethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 2-(4-chlorophenyl)-6-[(6-chloropyridin-3-yl)methyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 2-(4-chlorophenyl)-6-[4-(methylsulfonyl)benzyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 2-(1,3-benzodioxol-5-yl)-6-[3-(trifluoromethyl)benzyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 2-(1,3-benzodioxol-5-yl)-6-[(6-chloropyridin-3-yl)methyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 6-(3-chloro-4-fluorobenzyl)-2-(1-methylpiperidin-4-yl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 6-(3-chloro-4-fluorobenzyl)-2-(2-morpholin-4-ylethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 2-benzyl-6-(3-chloro-4-fluorobenzyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 2-(2-morpholin-4-ylethyl)-6-[3-(trifluoromethyl)benzyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 6-(3-chlorobenzyl)-2-(4-methoxybenzyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 3-[(2-benzyl-3-oxo-1,2,3,4,5,7-hexahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)sulfonyl]benzonitrile; 2-(4-chlorophenyl)-6-[(4-methylphenyl)sulfonyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 6-(1H-benzimidazol-2-ylmethyl)-2-benzyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 2-benzyl-6-(pyridin-3-ylsulfonyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 2-(2-methyl-1,3-benzothiazol-6-yl)-6-(pyridin-2-ylmethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 3-{[2-(4-cyanophenyl)-3-oxo-1,2,3,4,5,7-hexahydro-6H-pyrazolo[3,4-c]pyridin-6-yl]methyl}benzonitrile; 2-benzyl-6-[4-(methylsulfonyl)benzyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 2-(2-methyl-1,3-benzothiazol-6-yl)-6-(pyridin-3-ylmethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 6-(4-chlorobenzyl)-2-(2-morpholin-4-ylethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 3-{6-[(6-chloropyridin-3-yl)methyl]-3-oxo-1,3,4,5,6,7-hexahydro-2H-pyrazolo[3,4-c]pyridin-2-yl}benzonitrile; 2-benzyl-6-[(6-chloropyridin-3-yl)methyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 3-[3-oxo-6-(pyridin-3-ylmethyl)-1,3,4,5,6,7-hexahydro-2H-pyrazolo[3,4-c]pyridin-2-yl]benzonitrile; 6-(4-chlorobenzyl)-2-(2-methyl-1,3-benzothiazol-6-yl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; N-{3-[3-oxo-6-(pyridin-3-ylmethyl)-1,3,4,5,6,7-hexahydro-2H-pyrazolo[3,4-c]pyridin-2-yl]phenyl}acetamide; 6-(3-chloro-4-fluorobenzyl)-2-(2-methoxyethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 2-(2-methoxyethyl)-6-(pyridin-3-ylmethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 6-(3,5-dichlorobenzyl)-2-(2-morpholin-4-ylethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 2-(1-phenylethyl)-6-(pyridin-3-ylmethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 2-(4-chlorophenyl)-6-(pyridin-2-ylmethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 2-(2-chloro-4-fluorobenzyl)-6-(pyridin-3-ylmethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 6-(3-chlorobenzyl)-2-[1,2,4]triazolo[4,3-b]pyridazin-6-yl-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 6-(3-chlorobenzyl)-2-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 3-[(2-{5-[(4-methylpiperazin-1-yl}sulfonyl]pyridin-2-yl-3-oxo-1,2,3,4,5,7-hexahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methyl]benzonitrile; 6-(3-chloro-4-fluorobenzyl)-2-(4-chlorophenyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 2-(2-chloro-4-fluorobenzyl)-6-[(6-chloropyridin-3-yl)methyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 4-{6-[(6-chloropyridin-3-yl)methyl]-3-oxo-1,3,4,5,6,7-hexahydro-2H-pyrazolo[3,4-c]pyridin-2-yl}benzonitrile; 2-(2-chloro-4-fluorobenzyl)-6-[3-(trifluoromethyl)benzyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 6-(3-chloro-4-fluorobenzyl)-2-(2-methyl-1,3-benzothiazol-6-yl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 2-(2-methyl-1,3-benzothiazol-6-yl)-6-[3-(trifluoromethyl)benzyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 2-(2-benzyl-3-oxo-1,2,3,4,5,7-hexahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-N-methylacetamide; 3-{[2-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-oxo-1,2,3,4,5,7-hexahydro-6H-pyrazolo[3,4-c]pyridin-6-yl]methyl}benzonitrile; 2-benzyl-6-[(1-methyl-1H-pyrazol-3-yl)methyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 3-{6-[4-(methylsulfonyl)benzyl]-3-oxo-1,3,4,5,6,7-hexahydro-2H-pyrazolo[3,4-c]pyridin-2-yl}benzonitrile; 3-[6-(3-chloro-4-fluorobenzyl)-3-oxo-1,3,4,5,6,7-hexahydro-2H-pyrazolo[3,4-c]pyridin-2-yl]benzonitrile; 6-[(6-chloropyridin-3-yl)methyl]-2-(2-methyl-1,3-benzothiazol-6-yl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 3-{3-oxo-6-[3-(trifluoromethyl)benzyl]-1,3,4,5,6,7-hexahydro-2H-pyrazolo[3,4-c]pyridin-2-yl}benzonitrile; 6-[(6-chloropyridin-3-yl)methyl]-2-(2-fluorophenyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 4-[3-oxo-6-(pyridin-3-ylmethyl)-1,3,4,5,6,7-hexahydro-2H-pyrazolo[3,4-c]pyridin-2-yl]benzonitrile; N-(3-{6-[(6-chloropyridin-3-yl)methyl]-3-oxo-1,3,4,5,6,7-hexahydro-2H-pyrazolo[3,4-c]pyridin-2-yl}-phenyl)acetamide; 6-(3-chlorobenzyl)-2-[4-(trifluoromethyl)phenyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 6-(3-chlorobenzyl)-2-(4-chloro-2-fluorophenyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 6-(pyridin-3-ylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 2-(4-methoxyphenyl)-6-(pyridin-3-ylmethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 2-[3-(benzyloxy)phenyl]-6-[(4-methylphenyl)sulfonyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; N-{4-[(2-benzyl-3-oxo-1,2,3,4,5,7-hexahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methyl]phenyl}acetamide; 6-(3-chlorobenzyl)-2-(3-fluorobenzyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 6-(3-chlorobenzyl)-2-(4-fluorobenzyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 6-(3-chlorobenzyl)-2-[2-(dimethylamino)benzyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 5-[(2-benzyl-3-oxo-1,2,3,4,5,7-hexahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methyl]-2-fluorobenzonitrile; 2-benzyl-6-(quinolin-2-ylmethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 3-{[2-(2-methyl-1,3-benzothiazol-6-yl)-3-oxo-1,2,3,4,5,7-hexahydro-6H-pyrazolo[3,4-c]pyridin-6-yl]methyl}benzonitrile; 2-benzyl-6-[(6-chloropyridin-2-yl)methyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 2-benzyl-6-(3-methoxybenzyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 2-benzyl-6-(4-methoxybenzyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 2-benzyl-6-[(5-methylisoxazol-3-yl)methyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 6-(1,3-benzothiazol-2-ylmethyl)-2-benzyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 3-[6-(4-chlorobenzyl)-3-oxo-1,3,4,5,6,7-hexahydro-2H-pyrazolo[3,4-c]pyridin-2-yl]propanenitrile; 2-benzyl-6-[(3-fluorophenyl)sulfonyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 2-benzyl-6-[(3-methoxyphenyl)sulfonyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 2-benzyl-6-[(3-chlorophenyl)sulfonyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 2-benzyl-6-[(4-methoxyphenyl)sulfonyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 2-benzyl-6-[(4-chlorophenyl)sulfonyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 2-benzyl-6-[(4-fluorophenyl)sulfonyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 2-benzyl-6-[(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl)sulfonyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 2-benzyl-6-(quinolin-8-ylsulfonyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 3-{[3-oxo-2-(2-phenylethyl)-1,2,3,4,5,7-hexahydro-6H-pyrazolo[3,4-c]pyridin-6-yl]methyl}benzonitrile; 3-{[2-(4-methoxyphenyl)-3-oxo-2,3,3a,4,5,7-hexahydro-6H-pyrazolo[3,4-c]pyridin-6-yl]methyl}benzonitrile; 6-[(4-methylphenyl)sulfonyl]-2-(2-phenoxyethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 6-(3-chlorobenzyl)-2-(pyridin-4-ylmethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 6-[(4-methylphenyl)sulfonyl]-2-phenyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 2-(diphenylmethyl)-6-(pyridin-3-ylmethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 6-[(4-methylphenyl)sulfonyl]-2-(2-morpholin-4-ylethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 6-[(4-methylphenyl)sulfonyl]-2-(pyridin-2-ylmethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 6-[(4-methylphenyl)sulfonyl]-2-(1-methylpiperidin-4-yl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 2-(imidazo[1,2-a]pyridin-2-ylmethyl)-6-[(4-methylphenyl)sulfonyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 3-{6-[(4-methylphenyl)sulfonyl]-3-oxo-1,3,4,5,6,7-hexahydro-2H-pyrazolo[3,4-c]pyridin-2-yl}propanenitrile; 2-[2-(dimethylamino)benzyl]-6-[(4-methylphenyl)sulfonyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 6-[(4-methylphenyl)sulfonyl]-2-(pyridin-4-ylmethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 2-[2-(dimethylamino)ethyl]-6-[(4-methylphenyl)sulfonyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 2-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-6-(methylsulfonyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 6-[(3-chloro-4-fluorophenyl)sulfonyl]-2-(imidazo[1,2-a]pyridin-2-ylmethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 6-[(4-methylphenyl)sulfonyl]-2-quinoxalin-2-yl-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 6-[(4-methylphenyl)sulfonyl]-2-(pyridin-3-ylmethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 6-[(4-methylphenyl)sulfonyl]-2-pyridin-2-yl-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 6-[(3,4-dichlorophenyl)sulfonyl]-2-(imidazo[1,2-a]pyridin-2-ylmethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 2-(7-chloroquinolin-4-yl)-6-[(4-methylphenyl)sulfonyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; N-(3-{6-[(4-methylphenyl)sulfonyl]-3-oxo-1,3,4,5,6,7-hexahydro-2H-pyrazolo[3,4-c]pyridin-2-yl}phenyl)acetamide; 6-(biphenyl-4-ylsulfonyl)-2-(imidazo[1,2-a]pyridin-2-ylmethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 2-(imidazo[1,2-a]pyridin-2-ylmethyl)-6-{[3-(trifluoromethyl)phenyl]sulfonyl}-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 2-benzyl-6-(phenylsulfonyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 2-(2-morpholin-4-ylethyl)-6-(phenylsulfonyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 6-[(4-chlorophenyl)sulfonyl]-2-phenyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 2-benzyl-6-[(4-tert-butylphenyl)sulfonyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 2-(1-benzylpiperidin-4-yl)-6-[(4-methylphenyl)sulfonyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; 6-[(4-chlorophenyl)sulfonyl]-2-(2-morpholin-4-ylethyl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one; and 2-[2-fluoro-4-(methylsulfonyl)phenyl]-6-[(4-methylphenyl)sulfonyl]-1,2,4,5,6,7-hexahydro-3H-pyrazolo[3,4-c]pyridin-3-one.
 15. A pharmaceutical composition containing at least one compound according to claim 1 and a pharmaceutically acceptable carrier, diluent or excipient thereof.
 16. A method for treating a patient suffering from a disease or condition selected from cardiovascular disorders, respiratory disorders, metabolism disorders, skin disorders, bone disorders, neuroinflammatory and/or neurodegenerative disorders, kidney diseases, reproduction disorders, diseases affecting the eye and/or the lens and/or conditions affecting the inner ear, inflammatory disorders, liver diseases, pain, cancers allergic disorders, traumatisms, septic, hemorrhagic and anaphylactic shock, disorders of the gastrointestinal system, angiogenesis, angiogenesis-dependent conditions and other diseases and disorders associated with Nicotinamide adenine dinucleotide phosphate oxidase (NADPH Oxidase) wherein the method comprises administering a compound according to claim 1, in a patient in need thereof.
 17. A method for inhibiting angiogenesis in a patient in need thereof, wherein the method comprises administering an angiogenesis inhibiting dose of a compound according to claim 1, in a patient in need thereof.
 18. The method according to claim 16, wherein the disease or condition is a cancer.
 19. The method according to claim 18, wherein the compound is administered in combination with a co-agent useful in the treatment of cancer.
 20. The method according to claim 18, wherein the compound is administered in combination with radiation therapy. 